Gene genie

[Jo Bowyer]

Cellular Stress Response Gene Expression During Upper and Lower Body High Intensity Exercises

http://journals.plos.org/plosone/art...l.pone.0171247

Introduction

High intensity exercise causes metabolic changes on many levels of human body altering the production of interleukins and heat shock protein [1–3], the availability of substrates, activation of metabolic enzymes [4], and others. All these changes start at the level of gene transcription. It is now understood that changes in genes expression caused by exercises occur primarily in genes associates with apoptosis and inflammation [1]. Considerable evidence demonstrates the influence of various types of exercise on inflammation [5, 6] and the expression of genes encoding heat shock protein [7, 8], thereby mediating the health benefits of episodic and prolonged exercise. The health promoting effects of exercise are associated with production of interleukins, elicited anti-inflammatory response trough inflammation [1], and increased stress tolerance.

[marcel]

Nature | Outlook: Precision medicine

In this Supplement
Outlook
Related articles

Health care that is tailored on the basis of an individual’s genes, lifestyle and environment is not a uniquely modern concept. But advances in genetics and the growing availability of health data for researchers and physicians promise to make this new era of medicine more personalized than ever before.
Free full access =>

http://www.nature.com/nature/outlook...html#editorial

From:Nature Supplements archive (many free access papers)

http://www.nature.com/nature/archive/supplements.html

[marcel]

Let the structural symphony begin
Nature 2016

Like other structural biologists, Eva Nogales works in extraordinary times. The University of California, Berkeley, faculty member now has the tools to tackle important questions about cells' molecular machinery that would have been impossible to answer just a few years ago.

A recent project with Berkeley colleague Jennifer Doudna, the molecular biologist who co-pioneered the CRISPR–Cas9 gene-editing method, is a case in point. Both were intensely interested in the R-loop, a structure made of nucleic acids that forms in cells in many situations, but also just before DNA is snipped by CRISPR–Cas9. Nogales and her team revealed an R-loop in Streptococcus pyogenes bacteria, and from the near-atomic-resolution images, deduced how the Cas9 enzyme opens up the DNA conformation at specific sites and makes them accessible to CRISPR's molecular scissors1.

http://www.nature.com/nature/journal...l/536361a.html

The details of the enzyme RNA polymerase

[marcel]

A simpler twist of fate

Ways to directly convert one mature cell type into another may eventually offer a safer, faster strategy for regenerative medicine.
Nature 2016

Until the day it dies, a cell that has become a skin cell remains a skin cell — or so scientists used to think. Over the past decade, it has become clear that cellular identity is not written in stone but can be rewritten by activating specific genetic programs. Today, the field of regenerative medicine faces a question: should this rewriting take the conventional route, in which mature cells are first converted back into stem cells, or, where feasible, a more direct approach?

'Terminally differentiated' is a term that sums up the old way of thinking — that skin, muscle or other mature cells cannot be coaxed to adopt a drastically different fate. That idea began to falter a decade ago, when cell biologist Shinya Yamanaka of Kyoto University in Japan showed that a handful of genes could transform adult fibroblast (connective tissue) cells into induced pluripotent stem (iPS) cells1. Like embryonic stem cells, iPS cells can develop into any cell type, a property called pluripotency. They can also be produced in unlimited quantities, unlike embryonic stem cells, which must be harvested from human embryos and therefore come with considerable political baggage.

http://www.nature.com/nature/journal...l/534421a.html

[marcel]

The dark side of the human genome
Kelly Rae Chi
Nature aug. 2016

Fifteen years ago, scientists celebrated the first draft of the sequenced human genome. At the time, they predicted that humans had between 25,000 and 40,000 genes that code for proteins. That estimate has continued to fall. Humans actually seem to have as few as 19,000 such genes1 — a mere 1–2% of the genome. The key to our complexity lies in how these genes are regulated by the remaining 99% of our DNA, known as the genome's 'dark matter'.

So far, the data suggest that there are hundreds of thousands of functional regions in the human genome whose task is to control gene expression: it turns out that much more space in the human genome is devoted to regulating genes than to the genes themselves. Scientists are now trying to validate each predicted element experimentally to ascertain its function — a mammoth task, but one for which they now have a powerful new tool.

Since the gene-editing technique CRISPR–Cas9 entered the scientific arena, the speed at which researchers can test functional elements in the non-coding regions has ramped up. But it is still a daunting endeavour: more than 3 million regulatory DNA regions, thought to contain some 15 million binding sites for regulatory proteins called transcription factors, control gene expression in the human cell types studied thus far. About 150,000 may be active in any given cell type.

http://www.nature.com/nature/journal...l/538275a.html

[Jo Bowyer]

Laboratory and clinical genomic data sharing is crucial to improving genetic health care: a position statement of the American College of Medical Genetics and Genomics

Abstract

Keywords: genomic data sharing; genomic databases; gene variant databases; genotypehenotype correlations
There exist 5,000–7,000 rare genetic diseases, each of which harbors considerable clinical variability. None are common individually. In addition, more common diseases with genetic influences may have rare variants associated with them. Vast allelic heterogeneity lies at the foundation of most genetic diseases, the effects of which are compounded by background genomic variation that may further affect clinical presentation.

The considerable variation in clinical presentation and molecular etiology of genetic disorders, coupled with their relative individual rarity, makes it clear that no single provider, laboratory, medical center, state, or even individual country will typically possess sufficient knowledge to deliver the best care for patients in need of care. Even in the relatively rare situation in which pathogenic variants are few (e.g., sickle cell anemia), variants in other alleles may contribute to the genomic variation and clinical manifestations of disease. For more genetically complex conditions such as cystic fibrosis, in spite of decades of study, as many as 10% of cases have a CFTR variant so rare that it is represented in only one or two people in current databases, a situation paralleled in many genetic diseases.1,2

To ensure that our patients receive the most informed care possible, the American College of Medical Genetics and Genomics advocates for extensive sharing of laboratory and clinical data from individuals who have undergone genomic testing. Information that underpins health-care service delivery should be treated neither as intellectual property nor as a trade secret when other patients may benefit from the knowledge being widely available. It is similarly important for understanding the risks associated with genetic test results that place asymptomatic/presymptomatic individuals at high risk of developing a genetic disease. Sharing data in this precompetitive space will provide both a resource for clinical laboratories interpreting test results and clinical validity data that can benefit device manufacturers developing new tests and testing platforms. Contributing to public clinical databases in the precompetitive space recognizes that information about genetic diseases is dense and accumulating rapidly, and that information science is empowering the use of “big data.” Further, the shift to public databases being populated by de-identified case-level information from electronic health records will speed the time to “publication” of what are essentially case reports in real time. This process can also reduce the time period during which one might be able to protect trade secrets. Recognizing the importance of data sharing for both research and clinical care, the National Institutes of Health has established a genomic data-sharing policy for its funded investigators.3

Responsible sharing of genomic variant and phenotype data will provide the robust information necessary to improve clinical care and empower device and drug manufacturers that are developing tests and treatments for patients.

Broad data sharing is necessary and will improve care by making available the best data possible by which:

○ Key clinical attributes of the phenotype of those with genetic diseases can be described

○The qualitative strength of the association between genetic diseases and the underlying causative genes can be established

○ The classification of genomic variants across the range of benign to pathogenic can be established

○ Differences in variant interpretation among laboratories can be reconciled

○ The appropriate classification of variants of uncertain significance can be made
○ Standards used in variant classification can be improved


Data sharing will provide the scientific community, health-care providers, and industry with the best data on which:

○ Web-based systems for integrated clinical decision support are based

○ Secondary studies using these data are powered
Data sharing will offer significant financial benefits by which:

○ More standardized approaches to coverage and reimbursement policies can be made

○ The expensive duplication of previously resolved, but unpublished, research efforts currently occurring among pharmaceutical companies can be reduced
The analytical challenges of migrating and integrating clinical and laboratory data across the genome are daunting. Standardization of laboratory and clinical information will enable:


Data compatibility
Interoperability between information systems
Importantly, broad data sharing is compatible with the critical imperative of protecting the privacy of individual health-care information and the security of data systems holding that information. For data to be shared safely for patients and providers, systems are required that:

Ensure the security of databases, whether centralized or federated
Ensure the privacy of patient and family medical information
Provide transparency in the documentation of data-sharing transactions
Clinical-grade standards by which claims about gene/disease associations and the clinical significance of variants are made (e.g., data provenance, database versioning, and expert information curation) are central to a shared genomics data system. However, the need to deliver safe and effective care for those with or at risk for rare diseases, despite weak data for most variants and inevitable conflicts in data interpretation, requires balancing regulatory oversight with the need to provide services regardless of how well a rare disease is understood.

Due to the vast amount of data now being generated by genomic testing, genetic diseases will offer the opportunity to develop the framework for a national learning health-care system because the shared experiences of those caring for these patients continually contribute to improvements in delivering services to this population. A learning health-care system that facilitates access to diagnostic, treatment, and outcomes data to inform the care of today’s patients requires a paradigm shift in how we share data to be used in research and clinical practice. Academic medical centers have already begun to address how providers within their systems can use information about their patients to benefit other patients. This approach could be made national in scope to the benefit of patients everywhere. The National Institutes of Health has already made such data sharing a priority in the research that it funds. However, to accomplish these goals, and to ensure that the tremendous amounts of information now being generated are not wasted, our community must both demonstrate the will to share data broadly and develop the mechanisms to do so easily. These efforts will require support and participation from clinical laboratories, clinicians, regulatory agencies, researchers, and patients to ensure success in improving patient care through genomic medicine.

[marcel]

A few words from sapolsky, in the part before this he explains the "misunderstandings" (in plain english) of how genes work

https://aeon.co/essays/dead-or-alive...e-selfish-gene

It makes no sense to ask what a particular gene does
Robert Sapolsky

,....The environment can be the local cellular environment. Suppose oxygen radicals are accumulating in a cell, not a good thing. Scattered throughout the cell are copies of a class of sentinel transcription factors that are activated by oxygen radicals. Once activated, they head off to the DNA. There are a number of genes that code for antioxidants that mop up oxygen radicals, and just before the start of each is a promoter regulated by that transcription factor. So in this scenario, the genome inside this cell mobilises antioxidant defences in response to signals from the cellular environment.

The environment can be the environment of the body. Suppose a woman is secreting oestrogen from her ovaries during the latter half of her reproductive cycle. After coursing through the bloodstream, oestrogen will enter the uterine cells and bind to an oestrogen receptor. And this activated receptor now acts as… yes, a transcription factor. It binds to promoters ‘upstream’ of genes related to cell division. And as a result, new cells proliferate, the uterus thickens, preparing it for implantation of a fertilised egg. In this scenario, the genome inside this cell causes it to divide in response to a signal from a distant organ.

And the environment can be environment with a capital ‘E’, the outside world. Suppose a male antelope smells the pheromones of a threatening competitor. Through steps leading from the nose to the testes, he secretes testosterone. Which makes its way to a muscle cell, binds to a testosterone receptor, which acts as a transcription factor and activates genes related to cell growth, contributing to increased muscle mass. And thus in this scenario, the much-vaunted genome inside that cell is being regulated by some other guy’s pee.

It ultimately makes no sense to ask what a gene does, only what it does in a particular environment; remember what turns grasshoppers into locusts. It is the triumph of context.

[marcel]

http://phys.org/news/2016-12-junk-rn...-key-role.html

'Junk RNA' molecule found to play key role in cellular response to stress
December 15, 2016

A study from Massachusetts General Hospital (MGH) investigators has found a surprising role for what had been considered a nonfunctional "junk" RNA molecule: controlling the cellular response to stress. In their report in the Dec. 15 issue of Cell, the researchers describe finding that a highly specific interaction between two elements previously known to repress gene transcription—B2 RNA and EZH2, an enzyme previously known only to silence genes—actually induces the expression of stress-response genes in mouse cells.

"EZH2 is part of a structure called the Polycomb Repressive Complex 2, which silences target genes," says Jeannie T. Lee, MD, PhD,of the MGH Department of Molecular Biology, senior author of the report. "But a big paradox in the field has been that EZH2 is found at the sites of both active and inactive genes. We have shown, for the first time, that EZH2 can act outside of the PRC2 complex to activate genes through another mechanism—in this case by cleaving the B2 RNA molecule, which then activates stress response genes."

[marcel]

http://phys.org/news/2016-12-cogniti...orms.html#nRlv

New study shows cognitive decline may be influenced by interaction of genetics and...
30 dec. 2016

,.....The goal of this study, Trumble explains, was to reexamine the potentially detrimental effects of the globally-present ApoE4 allele in environmental conditions more typical of those experienced throughout our species' existence—in this case, a community of Amazonian forager-horticulturalists called the Tsimane.

"For 99% of human evolution, we lived as hunter gatherers in small bands and the last 5,000-10,000 years—with plant and animal domestication and sedentary urban industrial life—is completely novel,"

Due to the tropical environment and a lack of sanitation, running water, or electricity, remote populations like the Tsimane face high exposure to parasites and pathogens, which cause their own damage to cognitive abilities when untreated.

As a result, one might expect Tsimane ApoE4 carriers who also have a high parasite burden to experience faster and more severe mental decline in the presence of both these genetic and environmental risk factors.

But when the Tsimane Health and Life History Project tested these individuals using a seven-part cognitive assessment and a medical exam, they discovered the exact opposite.

In fact, Tsimane who both carried ApoE4 and had a high parasitic burden displayed steadier or even improved cognitive function in the assessment versus non-carriers with a similar level of parasitic exposure. The researchers controlled for other potential confounders like age and schooling, but the effect still remained strong. This indicated that the allele potentially played a role in maintaining cognitive function even when exposed to environmental-based health threats.

For Tsimane ApoE4 carriers without high parasite burdens, the rates of cognitive decline were more similar to those seen in industrialized societies, where ApoE4 reduces cognitive performance.

[Jo Bowyer]

Individual Cell Clocks and Immunity

http://jonlieffmd.com/blog/individua...9c0c4-90589721

Each cell has oscillating gene networks that somehow help organize, synchronize, and anticipate activity of the tissues and the entire organism. Energy from the sun is transformed into energy and material for the cell to use in sync to these rhythms. The rhythms also are related to how the cell develops in particular organs and responses to damage and distress. It is not yet clear how these individual unique 24 hour clocks in each cell translates to the rhythms of the entire animal. In evolution, the development of these clocks appears to be vital to provide the needed resources for DNA repair at the proper time of day. Also, it provides machinery at the right time to make oxygen and a way to avoid expending energy for little gain.

The two previous posts have described the discovery of individual clocks in each cell and the way individual cells interact with tissues and the brain clocks to regulate metabolism in the most efficient manner. This post describes the unique clocks in immune cells and how vital this is the response to infection and trauma. The next post will describe the central brain clocks that synchronize some of the circadian rhythms.

[Jo Bowyer]

MicroRNAs Associated with Shoulder Tendon Matrisome Disorganization in Glenohumeral Arthritis

http://journals.plos.org/plosone/art...l.pone.0168077

Abstract

The extracellular matrix (ECM) provides core support which is essential for the cell and tissue architectural development. The role of ECM in many pathological conditions has been well established and ECM-related abnormalities leading to serious consequences have been identified. Though much has been explored in regards to the role of ECM in soft tissue associated pathologies, very little is known about its role in inflammatory disorders in tendon. In this study, we performed microRNA (miRNA) expression analysis in the long head of the human shoulder biceps tendon to identify key genes whose expression was altered during inflammation in patients with glenohumeral arthritis. We identified differential regulation of matrix metalloproteinases (MMPs) that could be critical in collagen type replacement during tendinopathy. The miRNA profiling showed consistent results between the groups and revealed significant changes in the expression of seven different miRNAs in the inflamed tendons. Interestingly, all of these seven miRNAs were previously reported to have either a direct or indirect role in regulating the ECM organization in other pathological disorders. In addition, these miRNAs were also found to alter the expression levels of MMPs, which are the key matrix degrading enzymes associated with ECM-related abnormalities and pathologies. To our knowledge, this is the first report which identifies specific miRNAs associated with inflammation and the matrix reorganization in the tendons. Furthermore, the findings also support the potential role of these miRNAs in altering the collagen type ratio in the tendons during inflammation which is accompanied with differential expression of MMPs.

[Jo Bowyer]

Genetics Link Sleep Disturbances With Restless Leg Syndrome, Schizophrenia and Obesity

http://neurosciencenews.com/sleep-ge...ophrenia-5776/

The study looked at the biological controllers of sleep duration, insomnia and excessive daytime sleepiness and how they linked to the health and life histories of more than 112,000 people taking part in the world-leading UK Biobank study. Study participants reported their sleep duration, the degree of insomnia and daytime sleepiness, and then had their genes mapped. Other information about them, such as their weight and any diseases they suffered from, was also collected.

The researchers identified for the first time areas of the genome that are associated with sleep disturbance – including insomnia and excessive daytime sleepiness – and also discovered novel genetic links with several medical conditions, including restless legs syndrome, schizophrenia and obesity. The strongest genetic association for insomnia symptoms fell within a gene previously linked to restless legs syndrome – a nervous system disorder affecting around 1 in 20 people that leads to a strong urge to move one’s legs, which is often worse at night. Other gene regions were important for insomnia, but selectively in either men or women.

The team also identified genetic links between longer sleep duration and schizophrenia risk and between increased levels of excessive daytime sleepiness and measures of obesity (body mass index and waist circumference). The research also suggested that insomnia has shared underlying biology with major depression and abnormal glucose metabolism.

Insomnia not purely psychological condition: Insomnia genes found

https://www.sciencedaily.com/release...0612115358.htm

In a sample of 113,006 individuals, the researchers found 7 genes for insomnia. These genes play a role in the regulation of transcription, the process where DNA is read in order to make an RNA copy of it, and exocytosis, the release of molecules by cells in order to communicate with their environment. One of the identified genes, MEIS1, has previously been related to two other sleep disorders: Periodic Limb Movements of Sleep (PLMS) and Restless Legs Syndrome (RLS). By collaborating with Konrad Oexle and colleagues from the Institute of Neurogenomics at the Helmholtz Zentrum, München, Germany, the researchers could conclude that the genetic variants in the gene seem to contribute to all three disorders. Strikingly, PLMS and RLS are characterized by restless movement and sensation, respectively, whereas insomnia is characterized mainly by a restless stream of consciousness.

Genetic overlap with other characteristics

The researchers also found a strong genetic overlap with other traits, such as anxiety disorders, depression and neuroticism, and low subjective wellbeing. "This is an interesting finding, because these characteristics tend to go hand in hand with insomnia. We now know that this is partly due to the shared genetic basis," says neuroscientist Anke Hammerschlag (VU), PhD student and first author of the study.

Different genes for men and women

The researchers also studied whether the same genetic variants were important for men and women. "Part of the genetic variants turned out to be different. This suggests that, for some part, different biological mechanisms may lead to insomnia in men and women," says professor Posthuma. "We also found a difference between men and women in terms of prevalence: in the sample we studied, including mainly people older than fifty years, 33% of the women reported to suffer from insomnia. For men this was 24%."

The risk genes could be tracked down in cohorts with the DNA and diagnoses of many thousands of people. The UK Biobank -- a large cohort from England that has DNA available -- did not have information as such about the diagnosis of insomnia, but they had asked their participants whether they found it difficult to fall asleep or to have an uninterrupted sleep. By making good use of information from slaapregister.nl (the Dutch Sleep Registry), the UK Biobank was able, for the first time, to determine which of them met the insomnia profile. Linking the knowledge from these two cohorts is what made the difference.

Update 14/06/2017

[Jo Bowyer]

Cellular Clocks and Metabolism

http://jonlieffmd.com/blog/cellular-...02a54-90589721

The previous post described the unusual and unexpected finding that all cells have their own individual clock. It now appears that individual cells have a basic core genetic clock and then a wide range of ancillary oscillations with genetic loops that synchronize the unique metabolism and behavior of each cell, each tissue, and each organ. How all of these loops and cycles relate to each other and to the central clock that sends out neurological messages and hormones in a 24 cycle is just now being discovered. This post discusses the latest findings about metabolism, individual clocks, tissue clocks, and central clocks. The next post discusses unique clocks affecting immune function, and then a post will discuss brain clocks. See the previous post for background and an introduction to the concept that each cell has a clock. This is another layer of specific communication among all cells.

[Jo Bowyer]

Genes associated with persistent lumbar radicular pain; a systematic review

http://bmcmusculoskeletdisord.biomed...891-016-1356-5

Abstract

Background
The aim of the present study was to provide an overview of the literature addressing the role of genetic factors and biomarkers predicting pain recovery in newly diagnosed lumbar radicular pain (LRP) patients.

Methods
The search was performed in Medline OVID, Embase, PsycInfo and Web of Science (2004 to 2015). Only prospective studies of patients with LRP addressing the role of genetic factors (genetic susceptibility) and pain biomarkers (proteins in serum) were included. Two independent reviewers extracted the data and assessed methodological quality.

Results
The search identified 880 citations of which 15 fulfilled the inclusion criteria. Five genetic variants; i.e., OPRM1 rs1799971 G allele, COMT rs4680 G allele, MMP1 rs1799750 2G allele, IL1α rs1800587 T allele, IL1RN rs2234677 A allele, were associated with reduced recovery of LRP. Three biomarkers; i.e., TNFα, IL6 and IFNα, were associated with persistent LRP.

Conclusion
The present results indicate that several genetic factors and biomarkers may predict slow recovery in LRP. Still, there is a need for replication of the findings. A stricter use of nomenclature is also highly necessary.

[marcel]

The Circadian Clock in Cancer Development and Therapy

Most aspects of mammalian function display circadian rhythms driven by an endogenous clock. The circadian clock is operated by genes and comprises a central clock in the brain that responds to environmental cues and controls subordinate clocks in peripheral tissues via circadian output pathways. The central and peripheral clocks coordinately generate rhythmic gene expression in a tissue-specific manner in vivo to couple diverse physiological and behavioral processes to periodic changes in the environment. However, as the world industrialized, activities that disrupt endogenous homeostasis with external circadian cues have increased. This change in lifestyle has been linked to increased risk of diseases in all aspects of human health, including cancer. Studies in humans and animal models have revealed that cancer development in vivo is closely associated with the loss of circadian homeostasis in energy balance, immune function and aging that are supported by cellular functions important for tumor suppression including cell proliferation, senescence, metabolism and DNA damage response. The clock controls these cellular functions both locally in cells of peripheral tissues and at the organismal level via extracellular signaling. Thus, the hierarchical mammalian circadian clock provides a unique system to study carcinogenesis as a deregulated physiological process in vivo. The asynchrony between host and malignant tissues in cell proliferation and metabolism also provides new and exciting options for novel anti-cancer therapies.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4103166/