Gene genie

[Jo Bowyer]

Genome-Wide Scan Informed by Age-Related Disease Identifies Loci for Exceptional Human Longevity

http://journals.plos.org/plosgenetic...l.pgen.1005728

Abstract

We developed a new statistical framework to find genetic variants associated with extreme longevity. The method, informed GWAS (iGWAS), takes advantage of knowledge from large studies of age-related disease in order to narrow the search for SNPs associated with longevity. To gain support for our approach, we first show there is an overlap between loci involved in disease and loci associated with extreme longevity. These results indicate that several disease variants may be depleted in centenarians versus the general population. Next, we used iGWAS to harness information from 14 meta-analyses of disease and trait GWAS to identify longevity loci in two studies of long-lived humans. In a standard GWAS analysis, only one locus in these studies is significant (APOE/TOMM40) when controlling the false discovery rate (FDR) at 10%. With iGWAS, we identify eight genetic loci to associate significantly with exceptional human longevity at FDR < 10%. We followed up the eight lead SNPs in independent cohorts, and found replication evidence of four loci and suggestive evidence for one more with exceptional longevity. The loci that replicated (FDR < 5%) included APOE/TOMM40 (associated with Alzheimer’s disease), CDKN2B/ANRIL (implicated in the regulation of cellular senescence), ABO (tags the O blood group), and SH2B3/ATXN2 (a signaling gene that extends lifespan in Drosophila and a gene involved in neurological disease). Our results implicate new loci in longevity and reveal a genetic overlap between longevity and age-related diseases and traits, including coronary artery disease and Alzheimer’s disease. iGWAS provides a new analytical strategy for uncovering SNPs that influence extreme longevity, and can be applied more broadly to boost power in other studies of complex phenotypes.

[Jo Bowyer]

DNA methylation changes in plasticity genes accompany the formation and maintenance of memory

http://www.nature.com/neuro/journal/...l/nn.4194.html

Abstract

The ability to form memories is a prerequisite for an organism's behavioral adaptation to environmental changes. At the molecular level, the acquisition and maintenance of memory requires changes in chromatin modifications. In an effort to unravel the epigenetic network underlying both short- and long-term memory, we examined chromatin modification changes in two distinct mouse brain regions, two cell types and three time points before and after contextual learning. We found that histone modifications predominantly changed during memory acquisition and correlated surprisingly little with changes in gene expression. Although long-lasting changes were almost exclusive to neurons, learning-related histone modification and DNA methylation changes also occurred in non-neuronal cell types, suggesting a functional role for non-neuronal cells in epigenetic learning. Finally, our data provide evidence for a molecular framework of memory acquisition and maintenance, wherein DNA methylation could alter the expression and splicing of genes involved in functional plasticity and synaptic wiring.

[Jo Bowyer]

Identification of Vulnerable Cell Types in Major Brain Disorders Using Single Cell Transcriptomes and Expression Weighted Cell Type Enrichment

http://journal.frontiersin.org/artic...016.00016/full

The researchers from the University of Edinburgh’s Centre for Clinical Brain Sciences used advanced gene analysis techniques to investigate which genes were switched on in specific types of brain cells.

They then compared this information with genes that are known to be linked to each of the most common brain conditions — Alzheimer’s disease, anxiety disorders, autism, intellectual disability, multiple sclerosis, schizophrenia and epilepsy.

Their findings reveal that for some conditions, the support cells rather than the neurons that transmit messages in the brain are most likely to be the first affected.

Alzheimer’s disease, for example, is characterised by damage to the neurons. Previous efforts to treat the condition have focused on trying to repair this damage.

The study found that a different cell type — called microglial cells — are responsible for triggering Alzheimer’s and that damage to the neurons is a secondary symptom of disease progression.

[Jo Bowyer]

Overlapping signatures of chronic pain in the DNA methylation landscape of prefrontal cortex and peripheral T cells

http://www.nature.com/articles/srep19615

Abstract

We tested the hypothesis that epigenetic mechanisms in the brain and the immune system are associated with chronic pain. Genome-wide DNA methylation assessed in 9 months post nerve-injury (SNI) and Sham rats, in the prefrontal cortex (PFC) as well as in T cells revealed a vast difference in the DNA methylation landscape in the brain between the groups and a remarkable overlap (72%) between differentially methylated probes in T cells and prefrontal cortex. DNA methylation states in the PFC showed robust correlation with pain score of animals in several genes involved in pain. Finally, only 11 differentially methylated probes in T cells were sufficient to distinguish SNI or Sham individual rats. This study supports the plausibility of DNA methylation involvement in chronic pain and demonstrates the potential feasibility of DNA methylation markers in T cells as noninvasive biomarkers of chronic pain susceptibility.

Introduction

Chronic pain is one of the most common causes for disability worldwide, with significant global impact on patient quality of life. Despite enormous efforts to find new therapeutic strategies, effective treatments for chronic pain continue to be elusive1. There are also no effective ways to predict susceptibility to developing chronic pain in response to injury, which is essential for developing prevention strategies.

A critical question that has implications for further development of therapeutic approaches and diagnostics and predictive markers of chronic pain is whether chronic pain has a systemic manifestation, particularly in the peripheral immune system. Several reports have identified strong links between pain and transcriptional or epigenetic changes in the blood18,19,20. We have previously reported that behavioral experiences that are primarily targeted to the brain, such as maternal care, altered DNA in peripheral T cells11,21,22. We therefore examined here whether DNA methylation changes in T cells are associated with chronic pain and whether these overlap with changes in DNA methylation in the brain.

Discussion

Many of the dysregulated genes and pathways identified have been associated with the negative impact of chronic pain on anxiety, depression and cognition. Gene set analysis revealed enrichments in conditions including depression, anhedonia and long-term potentiation. Furthermore, many of the genes highlighted in Fig. 2 that are correlated with pain sensitivity are also implicated in depression and anhedonia, including the dopamine D2 receptor and the mu- and delta-opioid receptors, and inhibition of HDAC activity in the PFC has anti-depressant actions54. Finally, we highlight GRIN1, a subunit of the NMDA receptor, which has a central role in neuroplasticity throughout the CNS. We therefore propose that pain-related changes in DNA methylation are an important mechanism underlying the widespread changes in cortical structure and function observed in many human chronic pain conditions.

Our results implicate wide networks and gene pathways in chronic pain and for the first time show correlation between severity of pain and methylation states of numerous genes in multigenic nodes. While some of the methylation changes may be consequential to other upstream methylation changes, it is highly plausible that many of the changes play a causal role in chronic pain. We therefore hypothesize that the changes in methylation of the genes within networks of interrelated genes will impact the activity of cellular pathways associated with those genes and we speculate that the activity of these cellular pathways may contribute to pain severity. This complex landscape of changes poises challenges for establishing causality

The utility of DNA methylation biomarkers in neurology and psychiatry is dependent on whether informative changes could be found in peripheral tissues such as saliva or blood.

T cell infiltration has been described in the peripheral and central nervous system following nerve injury, the absence of T cells results in reduced hypersensitivity and differential methylation patterns in whole blood samples from humans is associated with altered pain sensitivity20,38,56. The cellular pathways and their potential upstream regulators (e.g. TNF, IL1B, TGFB1) associated with differentially methylated genes in T cells are involved in the maladaptive changes associated with allodynia and hyperalgesia as well as in pain chronicity38,40,41.

Body of evidence demonstrating that life experience results in broad changes in DNA methylation in blood cells is growing rapidly. For example, social economic position in humans57, maternal deprivation in rhesus monkeys11, maternal prenatal stress12,22,58, maternal depression21 and a history of childhood physical aggression are associated with broad DNA methylation signatures in blood57 or T-cells59 and brain21,22. The changes observed in the current study may not only contribute to chronic pain but also reflect the unrelenting stress of living with chronic pain. Therefore, the long-term changes in DNA methylation in T cells may play an active role in the pathophysiology of peripheral neuropathies by embedding the transient and chronic exposures to cytokines released after nerve injury in addition to serving as biomarkers of chronic pain.

Most of the promoters (72%) identified as differentially methylated in T cells after nerve injury were also affected in the brain. We identified modules of genes that co-vary in the two tissues. While the methylation profiles in some of these modules were affected in the same direction in the brain and the T cells, others went in opposite direction. This is consistent with the idea that the brain and the immune system play different roles in chronic pain.

Computational prediction models (penalized logistic and linear regressions) run on differentially methylated genes in T cells (FDR < 0.2) identified a set of 11 genes able to differentiate neuropathic animals from controls and a pair of two genes able to predict the mechanical hypersensitivity thresholds in both neuropathic animals and controls. These results suggest that T cell DNA methylation differences might be used in the future as biomarkers not only for the diagnosis and treatment of chronic pain but also for early prediction of high susceptibility to developing chronic pain. It is important to note in this context that discordance in pain sensitivity in identical twins was correlated with DNA methylation differences, including in the TRPA1 promoter, in white blood cells20.

In conclusion, these data suggest that persistent pain is associated with broad and highly organized organism-wide changes in DNA methylation, including two critical biological systems: the central nervous and immune systems.

This work also provides a possible mechanistic explanation for commonly observed comorbidities observed in chronic pain (i.e anxiety, depression). Finally, the sheer magnitude of the impact of chronic pain, particularly in the prefrontal cortex, illustrates the profound impact that living with chronic pain exerts on an individual. Beyond the example of chronic pain, the robust and highly organized DNA methylation changes seen here in response to nerve injury provides some of the strongest evidence to date that experience effects DNA methylation landscapes at large distances in time and space.

[Jo Bowyer]

Transcriptional Analysis of T Cells Resident in Human Skin

http://journals.plos.org/plosone/art...l.pone.0148351

Abstract

Human skin contains various populations of memory T cells in permanent residence and in transit. Arguably, the best characterized of the skin subsets are the CD8+ permanently resident memory T cells (TRM) expressing the integrin subunit, CD103. In order to investigate the remaining skin T cells, we isolated skin-tropic (CLA+) helper T cells, regulatory T cells, and CD8+ CD103- T cells from skin and blood for RNA microarray analysis to compare the transcriptional profiles of these groups. We found that despite their common tropism, the T cells isolated from skin were transcriptionally distinct from blood-derived CLA+ T cells. A shared pool of genes contributed to the skin/blood discrepancy, with substantial overlap in differentially expressed genes between each T cell subset. Gene set enrichment analysis further showed that the differential gene profiles of each human skin T cell subset were significantly enriched for previously identified TRM core signature genes. Our results support the hypothesis that human skin may contain additional TRM or TRM-like populations.

There are a number of ways to interpret our findings. The first is that the differences we observed between skin and blood T cells could be, wholly or partially, due to changes induced by the different microenvironments. It may be that gene expression is altered so that circulating T cells can enter and take up residence in the skin, with the initial changes then triggering downstream effects on cell behavior and effector function [34]. Moreover, since healthy skin contains numerous commensal microbes [35] extending even into the dermis [36], there would conceivably be a constant supply of antigens to stimulate T cell activation. These stimuli are not usually present in the circulation, which could result in a difference in activation status

[Jo Bowyer]

Intracellular mGluR5 plays a critical role in neuropathic pain

http://www.nature.com/ncomms/2016/16...omms10604.html

Abstract

Spinal mGluR5 is a key mediator of neuroplasticity underlying persistent pain. Although brain mGluR5 is localized on cell surface and intracellular membranes, neither the presence nor physiological role of spinal intracellular mGluR5 is established. Here we show that in spinal dorsal horn neurons >80% of mGluR5 is intracellular, of which ~60% is located on nuclear membranes, where activation leads to sustained Ca2+ responses. Nerve injury inducing nociceptive hypersensitivity also increases the expression of nuclear mGluR5 and receptor-mediated phosphorylated-ERK1/2, Arc/Arg3.1 and c-fos. Spinal blockade of intracellular mGluR5 reduces neuropathic pain behaviours and signalling molecules, whereas blockade of cell-surface mGluR5 has little effect. Decreasing intracellular glutamate via blocking EAAT-3, mimics the effects of intracellular mGluR5 antagonism. These findings show a direct link between an intracellular GPCR and behavioural expression in vivo. Blockade of intracellular mGluR5 represents a new strategy for the development of effective therapies for persistent pain.

[Jo Bowyer]

From genes to latrines: Vikings and their worms provide clues to emphysema

http://www.sciencedaily.com/releases...0204085109.htm

Summary:

The key to an inherited deficiency, predisposing people to emphysema and other lung conditions, could lie in their Viking roots. Archaeological excavations of Viking latrine pits in Denmark have revealed that these populations suffered massive worm infestations. The way that their genes developed to protect their vital organs from disease caused by worms has become the inherited trait which can now lead to lung disease in smokers.

LSTM's Professor Richard Pleass is senior author on the paper. He said: "Vikings would have eaten contaminated food and parasites would have migrated to various organs, including lungs and liver, where the proteases they released would cause disease."

In this latest paper the authors show that these deviant forms of A1AT bind an antibody called immunoglobulin E (IgE) that evolved to protect people from worms. The binding of A1AT to IgE prevents the antibody molecule from being broken down by such proteases.

"Thus these deviant forms of A1AT would have protected Viking populations, who neither smoked tobacco nor lived long lives, from worms." Continued Professor Pleass, "it is only in the last century that modern medicine has allowed human populations to be treated for disease causing worms. Consequently these deviant forms of A1AT, that once protected people from parasites, are now at liberty to cause emphysema and COPD."

[Jo Bowyer]

CHRONIC PAIN RELIEVED BY BLOCKING STRESS PROTEIN IN MICE

http://neurosciencenews.com/fkbp51-chronic-pain-3635/

The researchers studied genetically modified mice that lacked a protein called FKBP51. This protein is very important for regulating stress. Variations in the human FKBP5 gene are linked to the risk of developing stress-related psychiatric disorders, such as major depression and post-traumatic stress disorder (PTSD).

Previous studies have shown that people with specific FKBP5 variations feel greater physical pain after serious trauma, and the UCL team have now discovered that mice without FKBP51 experience reduced chronic pain from nerve damage and arthritic joints.

“Inhibiting FKBP51 has a very powerful effect in mice with chronic pain,” says lead author Dr Maria Maiarù (UCL Cell & Developmental Biology). “Not only does it block the pain from their injury without affecting their normal pain response, it also makes them more mobile. We did not find any negative side-effects.”

The team then tested an FKBP51-blocking compound called SAFit2, developed by Dr Felix Hausch at the Max Planck Institute of Psychiatry to treat mood disorders by acting in the brain to reduce anxiety. By selectively blocking FKBP51 in the spinal cord, the UCL researchers were able to test its effects on chronic pain independently of its known effects on the brain. They found that SAFit2 substantially alleviated chronic pain in mice, making it a promising candidate for drug development.

The study also showed that an injury can trigger long-term epigenetic changes in spinal cord sensory circuits. This in turn leads to increased production of FKBP51 which contribute to the body’s pain response.

“FKBP51 in the brain can prolong the stress response after trauma and we have found that it also exacerbates the pain response,” explains Dr Géranton. “Although this may have once had an evolutionary advantage in promoting survival, in our current lifestyles it can lead to chronic pain, depression and PTSD. Chronic pain affects 1 in 5 adults worldwide and there are currently no effective treatments, so we are extremely excited to have identified a new treatment target.”

[Jo Bowyer]

Genetic mechanisms control the linear scaling between related cortical primary and higher order sensory areas

http://elifesciences.org/content/4/e11416v2
Abstract

In mammals, the neocortical layout consists of few modality-specific primary sensory areas and a multitude of higher order ones. Abnormal layout of cortical areas may disrupt sensory function and behavior. Developmental genetic mechanisms specify primary areas, but mechanisms influencing higher order area properties are unknown. By exploiting gain-of and loss-of function mouse models of the transcription factor Emx2, we have generated bi-directional changes in primary visual cortex size in vivo and have used it as a model to show a novel and prominent function for genetic mechanisms regulating primary visual area size and also proportionally dictating the sizes of surrounding higher order visual areas. This finding redefines the role for intrinsic genetic mechanisms to concomitantly specify and scale primary and related higher order sensory areas in a linear fashion.

The neocortex is the most recently evolved part of the human brain. It is associated with higher thought processes, including language and the processing of information from our senses. Anatomically, the neocortex is organised into different regions called ‘primary areas’ and ‘higher order areas’, and perturbations to this organisation are associated with disorders such as autism.

There are many more higher order areas than primary areas in a mammalian brain. But, while primary areas are known to be specified by developmental genes in the embryo, little is known about how the development of higher order areas is controlled. Recent findings suggested that primary areas might themselves influence the emergence of higher order areas via a series of developmental events.

The mouse neocortex is patterned into functionally distinct fields that include the primary sensory areas (visual, somatosensory and auditory), which receive modality-specific sensory inputs from thalamocortical axons (TCAs) originating from nuclei of the dorsal thalamus (O'Leary et al., 2013). In the cortex, the connections of TCAs establish precise topographic representations (or maps) of the sensory periphery (Krubitzer and Kaas, 2005; O'Leary et al., 2013). Primary areas are flanked by higher order sensory areas (HO), which are interconnected with them and also contain topographic maps (Felleman and Van Essen, 1991). In mammals, this evolutionarily conserved general layout of the intra-areal neural circuits is responsible for the orderly progression of sensory information, sensory perception and the integration of higher cortical functions

The present findings address the mechanisms that specify and regulate the size of higher order sensory areas, an issue that has been largely neglected. They reveal a novel, prominent role for intrinsic genetic information in this process.

Our results further reveal that higher order areas do not have a fixed size. Rather their relative size is flexible. By using mouse models with bi-directional changes of V1 size as a model, our study revealed that higher order areas scale linearly together with their related primary sensory areas,

[Jo Bowyer]

Precision medicine: Can we afford it? Can we afford not to explore it?

https://www.sciencedaily.com/release...0308110010.htm

Imagine that the next time your doctor orders a round of tests, in addition to cholesterol and vitamin D, she also orders a genome sequence. It sounds like science fiction, but the day might come sooner than you think.

Precision medicine -- in which each patient's prevention and treatment decisions are tailored for them -- has been a buzzword in the health care industry recently. President Barack Obama launched his Precision Medicine Initiative, and other countries have similar projects underway.

With concerns about the cost of health care, though, can we afford precision medicine?

In certain instances, precision medicine can actually save money. For example, if patients can be screened for drug hypersensitivity before being prescribed certain drugs, they won't have to be treated later, which is better for patients and cuts down on costs. A similar approach works for choosing treatments.

The extended part of the trial I'm in as a patient will involve a genome sequence. The outcome measures they are looking at relate to measures to reduce cost of management of glaucoma and maximization of QOL. As I currently have excellent vision apart from the need for reading glasses, they are hoping to help me (and my descendents) keep it.

[Jo Bowyer]

Serotonin and Dopamine Gene Variation and Theory of Mind Decoding Accuracy in Major Depression: A Preliminary Investigation

http://journals.plos.org/plosone/art...l.pone.0150872

Abstract

Theory of mind–the ability to decode and reason about others’ mental states–is a universal human skill and forms the basis of social cognition. Theory of mind accuracy is impaired in clinical conditions evidencing social impairment, including major depressive disorder. The current study is a preliminary investigation of the association of polymorphisms of the serotonin transporter (SLC6A4), dopamine transporter (DAT1), dopamine receptor D4 (DRD4), and catechol-O-methyl transferase (COMT) genes with theory of mind decoding in a sample of adults with major depression. Ninety-six young adults (38 depressed, 58 non-depressed) completed the ‘Reading the Mind in the Eyes task’ and a non-mentalistic control task. Genetic associations were only found for the depressed group. Specifically, superior accuracy in decoding mental states of a positive valence was seen in those homozygous for the long allele of the serotonin transporter gene, 9-allele carriers of DAT1, and long-allele carriers of DRD4. In contrast, superior accuracy in decoding mental states of a negative valence was seen in short-allele carriers of the serotonin transporter gene and 10/10 homozygotes of DAT1. Results are discussed in terms of their implications for integrating social cognitive and neurobiological models of etiology in major depression.

Neurons’ Faulty Wiring Leads to Serotonin Imbalance and Depressive Behaviors: Mouse Study

http://neurosciencenews.com/serotoni...pression-6524/

Summary:

Researchers have identified a gene that allows serotonin neurons to spread their branches throughout the brain. Mice lacking this gene showed entangled neuron branches and signs of depression.

Update 27/04/2017

[Jo Bowyer]

Why is There No Cure For Huntington’s

http://jonlieffmd.com/blog/why-is-th...22019-90589721

With extensive PR, the Genome Project promised rapid cures for many diseases by deciphering the genetic code for less than 2% of the human DNA involved in making proteins in a small number of people. After the Genome Project, there were almost no cures found in that code. In the decade after the project, research increasingly showed the fantastic complexity of the regulation of that tiny percentage of our DNA in a region at least ten times larger than the “genes.” (See posts on genetic complexity) It, also, showed that many differences in code exist between normal individuals. Millions of regulatory RNAs were discovered. The massive use of alternative splicing in the human brain was discovered. It, also, was found that in diseases that are based on a series of mutations, such as cancer, there are many individual variations in the mutations causing the same disease. Many diseases have large numbers of genes that are somehow related and not understood—autism, schizophrenia as examples. Also, it was found that fifty percent of the total DNA is “jumping genes” (see post) with critical effects on normal brain function and human brain evolution.

A cautionary tale of the promise of curing disease through identifying the genes involved is found by studying Huntington’s—a devastating neurodegenerative disease with a dominant gene that has been known for twenty-three years. Dominant gene means that anyone with one copy of the gene from either mother or father gets the disease. A burning question must be asked: why is there no cure for Huntington’s a generation after identifying the gene involved.

The fantastic complexity of human DNA is just beginning to unravel. As an example, this post will describe the current knowledge about Huntington’s and why there is no cure yet.

[Jo Bowyer]

Study Reveals Autism Genes Are in All of Us

http://neurosciencenews.com/autism-g...elopment-3889/

The researchers studied whether there is a genetic relationship between ASD and the expression of ASD-related traits in populations not considered to have ASD. Their findings, published this week in Nature Genetics, suggest that genetic risk underlying ASD, including both inherited variants and de novo influences (not seen in an individual’s parents), affects a range of behavioural and developmental traits across the population, with those diagnosed with ASD representing a severe presentation of those traits.

Autism spectrum disorders (ASD) are a class of neurodevelopmental conditions affecting about 1 in 100 children. They are characterised by social interaction difficulties, communication and language impairments, as well as stereotyped and repetitive behaviour. These core symptoms are central to the definition of an ASD diagnosis but also occur, to varying degrees, in unaffected individuals and form an underlying behavioural continuum.

With recent advances in genome sequencing and analysis, a picture of ASD’s genetic landscape has started to take shape. Research has shown that most ASD risk is polygenic (stemming from the combined small effects of thousands of genetic differences, distributed across the genome). Some cases are also associated with rare genetic variants of large effect, which are usually de novo.

[Jo Bowyer]

Nucleus accumbens D2R cells signal prior outcomes and control risky decision-making

http://www.nature.com/nature/journal...ture17400.html

A marked bias towards risk aversion has been observed in nearly every species tested1, 2, 3, 4. A minority of individuals, however, instead seem to prefer risk (repeatedly choosing uncertain large rewards over certain but smaller rewards), and even risk-averse individuals sometimes opt for riskier alternatives2, 5. It is not known how neural activity underlies such important shifts in decision-making—either as a stable trait across individuals or at the level of variability within individuals. Here we describe a model of risk-preference in rats, in which stable individual differences, trial-by-trial choices, and responses to pharmacological agents all parallel human behaviour. By combining new genetic targeting strategies with optical recording of neural activity during behaviour in this model, we identify relevant temporally specific signals from a genetically and anatomically defined population of neurons. This activity occurred within dopamine receptor type-2 (D2R)-expressing cells in the nucleus accumbens (NAc), signalled unfavourable outcomes from the recent past at a time appropriate for influencing subsequent decisions, and also predicted subsequent choices made. Having uncovered this naturally occurring neural correlate of risk selection, we then mimicked the temporally specific signal with optogenetic control during decision-making and demonstrated its causal effect in driving risk-preference. Specifically, risk-preferring rats could be instantaneously converted to risk-averse rats with precisely timed phasic stimulation of NAc D2R cells. These findings suggest that individual differences in risk-preference, as well as real-time risky decision-making, can be largely explained by the encoding in D2R-expressing NAc cells of prior unfavourable outcomes during decision-making.

I find risk takers fascinating,

[Jo Bowyer]

The ups and downs of transportation within cells New role for Rab6

https://www.sciencedaily.com/release...0405110505.htm

How do cells avoid growing topsy-turvy, growing so your top, front, bottom and back all wind up on the correct side requires a good sense of direction at the cellular level? A research group has identified a familiar gene with an unexpected role in directing proteins around the cell.