Gene genie

[Jo Bowyer]

Why fathers don't pass on mitochondria to offspring

https://www.sciencedaily.com/release...0623145932.htm

Offering insights into a long-standing and mysterious bias in biology, a new study reveals how and why mitochondria are only passed on through a mother's egg -- and not the father's sperm. What's more, experiments from the study show that when paternal mitochondria persist for longer than they should during development, the embryo is at greater risk of lethality.

[Jo Bowyer]

Genome-wide redistribution of MeCP2 in dorsal root ganglia after peripheral nerve injury

http://epigeneticsandchromatin.biome...072-016-0073-5

Background

Epigenetic modifications resulting from DNA methylation play a critical role in cellular differentiation, development [1] and may contribute to disease including peripheral and central pain sensation and processing [2]. DNA methylation is mediated by DNA methyltransferase (DNMT) catalyzing the transfer of a methyl group onto the 5′ position of cytosine. MeCP2 can decipher methylation patterns across the genome before binding to methylated DNA [1] and can mediate downstream transcriptional changes of a large number of genes [3]. Depending on its interacting protein partners and target genes, MeCP2 can act as either an activator or repressor [4]. MeCP2 can also play a role in dampening genome-wide transcriptional noise in a DNA methylation-dependent manner [5]. Mutations in MECP2 result in the neurodevelopmental disorder Rett syndrome (RTT) [6]. Among the many symptoms associated with RTT, alterations in pain sensitivity are reported to be as high as 75 % [7]. Reduced sensitivity has been observed in mouse models with RTT and autism-associated mutations [8, 9, 10, 11]. The observations from RTT patients and MeCP2-mutant mice indicate that MeCP2 contributes either directly or indirectly to reduced pain sensitivity.

Our previous study has shown that MeCP2 expression was altered in mouse dorsal root ganglia (DRG) following spared nerve injury (SNI). While we observed upregulation of MeCP2 protein 4 weeks post-surgery [10], others have reported downregulation at earlier time points and in subsets of damaged neurons in the DRG [11, 12]. MeCP2 has previously been linked to inflammatory pain. Inflammatory stimulus was shown to increase phosphorylation of MeCP2 in lamina I neurons in the dorsal horn, resulting in its dissociation from the genome, thereby alleviating repression of genes linked to pain [13]. MeCP2 has also been associated with central mechanisms of pain through regulation of a transcriptional repressor, histone dimethyltransferase G9a, resulting in increased expression of brain-derived neurotrophic factor [14].

MeCP2 is highly expressed in neurons and glia [5]. The dynamic expression of MeCP2 in the DRG after nerve injury [10] suggests a role for MeCP2 in pain modulation through transcriptional regulation. DRG are major players responsible for conveying noxious stimuli from the periphery to the central nervous system. MeCP2 is predominantly a nuclear protein and cell bodies of nociceptive sensory neurons are located in DRG, with two axonal branches projecting to the periphery and to the dorsal horn of the spinal cord. Genome-wide studies investigating MeCP2 binding patterns have been conducted in neurons, astrocytes and different regions of the brain [5, 15, 16, 17]. To investigate the role of MeCP2 in mediating nociception, and to determine changes in MeCP2 binding patterns after nerve injury, we performed chromatin immunoprecipitation followed by massively parallel sequencing (ChIP-seq) in mouse DRG 4 weeks after SNI surgery. We observed a genome-wide redistribution of MeCP2 binding and evaluated how changes in binding patterns directly and indirectly regulate genes that contribute to the pathology of pain.

[Jo Bowyer]

Single-cell genomics: coming of age

http://genomebiology.biomedcentral.c...ource=Teradata

Single-cell genomics is the study of the individuality of cells using omics approaches. Although young, the field has now entered its teenage years and is beginning to show clear signs of maturity. Its origins can be traced back to pioneering experiments that allowed the detection of gene expression in single cells by microarrays (reviewed in [1]). However, it was with the emergence of “next-generation” DNA sequencing that single-cell genomics really took off [2, 3, 4]. Although initial experiments were modest in size and resulted in noisy and incomplete data, they immediately revealed the great potential for biological discoveries. It soon became clear that the substantial technical and biological variability required data from many single cells in order to allow meaningful data mining and interpretation of the data [5]. Thus, the following years were spent pursuing a few lines of development: improvements in the accuracy and scope of single-cell methods and increasing throughput and reducing cost. Today, we are in a position to routinely measure gene expression in tens of thousands of single cells with high accuracy in terms of quantification of gene expression (albeit sensitivity in terms of detection of mRNAs varies significantly depending on protocol and sequencing depth). The costs are at least manageable and continue to decrease.

While single-cell RNA-seq is now mature and almost routine, technological development has shifted to other modalities: DNA, protein, chromatin modifications, and more. Single-cell whole-genome DNA sequencing is challenging because loss of material causes dropouts in the sequence and because sequencing errors are difficult to distinguish from real mutations. Despite these challenges, single human cortical neurons have been used to reconstruct lineages based on somatic mutations that had accumulated during development [6]. Similarly, clonal evolution within solid tumors can be revealed by detecting somatic copy number variations in single cells (reviewed in [7]).

Another trend is the extension of single-cell analysis to measure epigenetic states such as DNA accessibility [8, 9, 10], methylation [11], and chromosome conformation [12]. Generally these methods pose similar challenges to DNA sequencing but offer access to pure cellular epigenetic states that are simply inaccessible by bulk methods.

Single-cell protein analysis occupies a different niche, where smaller numbers of proteins can be analyzed but in very large numbers of cells, classically using fluorescence-activated cell sorting (FACS) for up to eight targets but more recently with mass cytometry targeting up to hundreds of proteins [13]. A limiting factor for protein analysis remains the requirement for high-quality affinity reagents such as antibodies.

Finally, a recent development (but see [14]) is the combination of methods to simultaneously measure two or more modalities in single cells. For example, genome and transcriptome [15, 16], transcriptome and methylome [17, 18], and RNA and protein [19]. In the near future, such experiments will be able to link the phenotypes of single cells evolving in tumors to their genotypes.

Due to the speed with which single-cell genomics technologies are evolving, computational analysis methods are racing to keep up. Statistical and computational methods are at the heart of single-cell genomics and are critical to extracting meaningful information and biology from the data. Much work has focused on transcriptomic data analysis (e.g., reviewed in [20]) and in this special issue of Genome Biology there are examples of areas that benefit from bespoke computational approaches at the levels of both cells and genes. In terms of individual genes, a method to define significant differences in the cell-to-cell variation in gene expression (as opposed to mean expression levels) is reported [21] and one paper addresses expression states of long noncoding RNAs [22]. In terms of cell-to-cell variation at the DNA level, there is clearly tremendous scope for computational method innovation in the area of tumor heterogeneity, addressed by Beerenwinkel and colleagues [23], and Markowetz and Ross [24] in this issue.

[Jo Bowyer]

Why We're Different

https://www.edge.org/conversation/ro...were-different

ROBERT PLOMIN is a professor of behavioral genetics at King's College London and deputy director of the Social, Genetic and Developmental Psychiatry Centre at the Institute of Psychiatry, Psychology and Neuroscience.

People understand heredity. When we talk about heredity, we're talking about eye color, hair color, height, those differences among us that are caused by DNA differences we inherit at the moment of conception. Behavioral genetics uses genetics to understand behavior. That's different from what a biologist would do, or a geneticist.

What I'm excited about now is the impact of the DNA revolution on the behavioral sciences and on society. It's an endgame for me, in terms of forty years of my research looking at genetic influences in the behavioral sciences. It's good to look at this in the perspective of forty years, and it's personal to me because it's been my journey. It might be hard for people to believe this, but forty years ago it was dangerous to talk about genetic influence in psychology.

As a graduate student at the University of Texas at Austin, my first meeting was the Eastern Psychological Association meeting in Boston. There I was, a naïve graduate student, at this meeting where I was presenting some work on behavioral genetics, which, at that time, was a twin study of personality development in children. I went to this plenary session with 3000 psychologists. Leon Kamin, who was president at that time, was giving his presidential address. He was thundering on about these wicked people daring to study genetics in psychology when we "know" that genetics doesn't have anything to do with it; it's all environmental. That was a real shocker to me because it was a rabble-rousing meeting, and the rabble was getting roused. I was the only behavioral geneticist in the audience.

That was my introduction to how political some of this was at the time and how much antipathy there was toward genetics. Things have changed quite a bit over the years. Forty years ago, the task was just to get people to consider the possibility that genetics might be important. Schizophrenia, for example, was mother blaming. The view back then was that it was caused by what your mother did to you in the first few years of life.

Twenty years ago I decided that we didn't need much more research demonstrating genetic influence. Twin studies and adoption studies made a solid case that just about everything showed genetic influence. We're talking about individual differences in behavior and the extent to which genetic factors explain these differences. Genetic influences aren't just significant; they're substantial. At that time—twenty years ago—I began to feel that some people would never believe this. But now we are starting to show genetic influence on individual differences using DNA. DNA is a game changer; it's a lot harder to argue with DNA than it is with a twin study or an adoption study.

[Jo Bowyer]

Growing Neurons Undergo Major Metabolic Shift

http://neurosciencenews.com/metaboli...oscience-4665/

Our brains can survive only for a few minutes without oxygen. Salk Institute researchers have now identified the timing of a dramatic metabolic shift in developing neurons, which makes them become dependent on oxygen as a source of energy.

[Jo Bowyer]

Role of astrocyte-synapse interactions in CNS disorders

http://onlinelibrary.wiley.com/doi/1...cceptedarticle

Abstract

Astrocytes comprise half of the cells in the brain. Although astrocytes have traditionally been described as playing a supportive role for neurons, they have recently been recognized as active participants in the development and plasticity of dendritic spines and synapses. Astrocytes can eliminate dendritic spines, induce synapse formation, and regulate neurotransmission and plasticity. Dendritic spine and synapse impairments are features of many neurological disorders, including autism spectrum disorder (ASD), schizophrenia, and Alzheimer's disease (AD). In this review we will present evidence from multiple neurological disorders demonstrating that changes in astrocyte-synapse interaction contribute to the pathology. Genomic analysis has connected altered astrocytic gene expression with synaptic deficits in a number of neurological disorders. Alterations in astrocyte-secreted factors have been implicated in the neuronal morphology and synaptic changes seen in neurodevelopmental disorders, while an alteration in astrocytic glutamate uptake is a core feature of multiple neurodegenerative disorders. This evidence clearly demonstrates that maintaining astrocyte-synapse interaction is crucial for normal central nervous system functioning. Obtaining a better understanding of the role of astrocytes at synapses in health and disease will provide a new avenue for future therapeutic targeting.

via @SimonGandevia

[Jo Bowyer]

Diseases that run in families not all down to genes, study shows

https://www.sciencedaily.com/release...0720105251.htm

Factors that are common to the family environment -- such as shared living space and common eating habits -- can make a major contribution to a person's risk of disease, the study found.

A study of common diseases in families across the UK has highlighted the importance of such factors in estimating a person's risk for diseases such as high blood pressure, heart disease and depression.

Previous studies have identified genes that are linked to numerous medical conditions, yet these only account for part of a person's likelihood of developing disease.

Researchers led by the University of Edinburgh's Roslin Institute and MRC Human Genetics Unit examined the medical histories of more than 500,000 people and their families -- including both blood and adoptive relatives.

They looked at incidents of 12 common diseases including high blood pressure, heart disease, and several cancers and neurological diseases.

By not accounting for shared environmental factors, scientists may overestimate the importance of genetic variation by an average of 47 per cent, the study found.

Experts say their findings will help to provide realistic expectations of the value of genetic testing for identifying people at risk of disease.

The research also underlines the need to identify environmental factors that contribute to diseases and how to modify them to reduce disease risk.

The study published in Nature Genetics, used data from the UK Biobank, a UK database of volunteers' health.

[Jo Bowyer]

Enrichment of risk SNPs in regulatory regions implicate diverse tissues in Parkinson’s disease etiology

http://www.nature.com/articles/srep30509

Introduction

Parkinson’s disease (PD) is the second most common neurodegenerative disorder, affecting about 1% of those over the age of 60. Classically, PD was considered a movement disorder with akinesia, rigidity, tremor and postural instability as the predominant motor features. More recently, it became clear that patients also experience a wide range of disabling nonmotor disturbances, e.g. olfactory deficits, sleep disorders, depression, cognitive decline, constipation and other autonomic changes1. The neuropathology is characterized by severe degeneration of substantia nigra dopaminergic neurons (crucial for the motor deficits) and progressive development of intraneuronal α-synuclein aggregates throughout the central and peripheral nervous systems2. Monogenetic forms of PD are rare and only account for 5–10% of cases3 (see also longer reviews4,5,6); a total of 7 autosomal and recessive genes have been identified, exhibiting varying degrees of penetrance. Thus, the vast majority of cases of PD are sporadic and a combination of environmental factors and complex genetic loci likely play a causative role4. In addition to the rare Mendelian-inherited cases of PD, the genetic predisposition to PD includes at least 26 common single nucleotide polymorphism (SNP) variants (“index SNPs”), each imposing low but significant risk7,8. These risk loci associated with PD were discovered by population-based genome-wide association studies (GWAS), published in 2014 in a comprehensive large-scale meta-analysis of reproducible hits7 and conveniently summarized in a Cell snapshot3. Importantly, most (>90%) of the identified index SNPs in PD GWAS7,8 are located in noncoding DNA regions, making the assignment of potential functionality or causality-even the identification of the specific genes associated with the risk-SNPs-quite challenging.

Since 2005, over 1,600 significant SNP risk variants have been identified by GWAS for more than 250 traits, many with complex genetic predisposition and unknown gene involvements (https://www.genome.gov/26525384). Most genetic epidemiological studies have attempted to characterize the risk SNPs found in non-coding DNA simply by considering the “nearest gene” as the one being involved in risk. However, many index SNPs and their surrogates [in linkage disequilibrium (LD)] reside in regulatory regions (mainly in enhancers) and the target genes of such regulation are most likely not the nearest genes9. Therefore, there is still a significant gap between the identification of most risk SNPs and an understanding of their biological function in human disease. Here, we have addressed this conundrum via the development and use of two Bioconductor software tools, FunciSNP and motifbreakR10,11, to functionally annotate risk SNPs for PD. The approach allows the identification of risk SNP enrichment at active regulatory elements in non-coding DNA (promoters and enhancers, in this study). Enrichment is defined as the presence of risk SNPs nonrandomly distributed and at an increased prevalence within chromatin regions with putative functions. The two alleles of the SNP may each impose a differential risk by affecting the regulatory capacity of the region on target genes.

In the past, we and others have used bioinformatic tools, including FunciSNP and motifbreakR, to interrogate genetic studies in light of both public and in-house next generation sequencing data. Noncoding risk regions of many complex diseases have thus been investigated in recent years. However, in most cases, this was done only in one specific cell- or tissue type within databases. More recently, with the curation of epigenetic data within the Roadmap Epigenomics Mapping Consortium (REMC), the mapping of risk alleles in a variety of cell types12 became possible. Thus, our present approach is based on the assessment of PD risk SNP enrichment at specific chromatin regulatory regions in multiple distinct cell- and tissue types. Twenty-one PD risk loci were assessed in 77 REMC cell types of diverse tissue- and lineage-origin. Eight enhancers at the four most significantly enriched PD risk loci were annotated in detail. They were found respectively in lymphocytes, mesendoderm, brain-, liver- and fat cells, allowing refined hypotheses to be formulated for the genetic predisposition to PD at these loci.

[Jo Bowyer]

How a Single Gene May Protect Against Causes of Neurodegenerative Diseases

http://neurosciencenews.com/genetics...diseases-4768/

New research has identified how cells protect themselves against ‘protein clumps’ known to be the cause of neurodegenerative diseases including Alzheimer’s, Parkinson’s and Huntington’s disease.

The study was done using a custom-built laboratory device that can compress neurons inside 3-D cell cultures while using a powerful microscope to continuously monitor changes in cell structure.

The study, which is published today in Cell and was conducted by the University of Glasgow in collaboration with the MRC Protein Phosphorylation and Ubiquitylation Unit at the University of Dundee, offers an insight into the role of a gene called UBQLN2 and how it helps to remove toxic protein clumps from the body and protect it from disease.

Using biochemistry, cell biology and sophisticated mouse models, the researchers discovered that the main function of UBQLN2 is to help the cell to remove dangerous protein clumps – a role which it performs by first detangling clumps, then shredding them to prevent future tangles.

Protein clumps occur as part of the natural aging process, but are normally detangled and disposed of as a result of the gene UBQLN2. However when this gene mutates, or becomes faulty, it can no longer help the cell to remove these toxic protein clumps, which leads to neurodegenerative disease.

Dr Thimo Kurz, from the Institute of Molecular, Cell and Systems Biology, said: “The function of UBQNL2 is connected to many neurodegenerative disorders, such as Parkinson’s, Alzheimer’s and Huntington’s disease.

“These patients often have very clear clumps in their brain cells. Using mice that mimic human Huntington’s disease, we found that when UBQLN2 is mutated, it could no longer help nerve cells to remove protein clumps in the brains of these mice.”

UBQLN2 Mediates Autophagy-Independent Protein Aggregate Clearance by the Proteasome
http://www.cell.com/cell/fulltext/S0092-8674(16)30866-2

[Jo Bowyer]

A Conserved MicroRNA Regulatory Circuit Is Differentially Controlled during Limb/Appendage Regeneration

http://journals.plos.org/plosone/art...l.pone.0157106

Abstract

Background

Although regenerative capacity is evident throughout the animal kingdom, it is not equally distributed throughout evolution. For instance, complex limb/appendage regeneration is muted in mammals but enhanced in amphibians and teleosts. The defining characteristic of limb/appendage regenerative systems is the formation of a dedifferentiated tissue, termed blastema, which serves as the progenitor reservoir for regenerating tissues. In order to identify a genetic signature that accompanies blastema formation, we employ next-generation sequencing to identify shared, differentially regulated mRNAs and noncoding RNAs in three different, highly regenerative animal systems: zebrafish caudal fins, bichir pectoral fins and axolotl forelimbs.

Results

These studies identified a core group of 5 microRNAs (miRNAs) that were commonly upregulated and 5 miRNAs that were commonly downregulated, as well as 4 novel tRNAs fragments with sequences conserved with humans. To understand the potential function of these miRNAs, we built a network of 1,550 commonly differentially expressed mRNAs that had functional relationships to 11 orthologous blastema-associated genes. As miR-21 was the most highly upregulated and most highly expressed miRNA in all three models, we validated the expression of known target genes, including the tumor suppressor, pdcd4, and TGFβ receptor subunit, tgfbr2 and novel putative target genes such as the anti-apoptotic factor, bcl2l13, Choline kinase alpha, chka and the regulator of G-protein signaling, rgs5.

Conclusions

Our extensive analysis of RNA-seq transcriptome profiling studies in three regenerative animal models, that diverged in evolution ~420 million years ago, reveals a common miRNA-regulated genetic network of blastema genes. These comparative studies extend our current understanding of limb/appendage regeneration by identifying previously unassociated blastema genes and the extensive regulation by miRNAs, which could serve as a foundation for future functional studies to examine the process of natural cellular reprogramming in an injury context.

[Jo Bowyer]

How epigenetics regulate vital functions from bacteria to humans

https://www.sciencedaily.com/release...0804141246.htm

A new study published by Boston University School of Medicine researchers in the journal of Genetics and Epigenetics, provides a comparative analysis of the evolution of epigenetic mechanisms from prokaryotes (bacteria) to simple eukaryotes (multi-cellular) to more complex eukaryotes (humans). Bacteria evolved billions of years ago, and even at that early stage, nature started the process of allowing bacterial DNA to perform different functions without changing the order by which DNA is organized. This was achieved by adding a chemical 'tag' to one of the subunits of DNA. The group of atoms that gets attached can vary based on the organism. This simple modification is important for bacterial survival, and allows bacteria to fight infections. It is striking though that the attachment site of the 'tag' shifted to a different subunit on DNA as eukaryotes developed. Viruses also learned how to use this "tagging" process to their advantage. The virus HIV, which causes AIDs, hides from an individual's immune system by removing a particular 'tag' from the proteins that fold DNA.

According to corresponding author Sibaji Sarkar, PhD, instructor of medicine at BUSM, it is intriguing to observe how nature shifted the site of 'tag' addition from bacteria to mammals. "The addition of 'tagging' proteins that are involved in folding DNA in eukaryotes provided another dimension," he explains.

He adds, "If we closely observe the process of regeneration in some eukaryotes including zebra fish, when a portion is cut out, it is clear that the present gene pool in the DNA provides the necessary healing process to regenerate the section of the organism. We may gain tremendous knowledge to understand how stem cells can become so many types of organs by studying this process." It appears that epigenetic mechanisms regulate this process. The most striking event which describes this type of multifaceted formation of organs and tissues from one cell (fertilized egg) is embryogenesis.

When mammals reproduce, the DNA sequences that are inherited cannot be altered, but from the time that the sperm fertilizes the egg, every step proceeds according to a set of rules until the tissues and organs are differentiated. Different sets of genes are used for each step of development. For example, the 'tags' in the egg are erased after fertilization and then rewritten. The proteins that rewrite this process are governed by the same proteins that fold the DNA in the mother's egg. It is reasonable, therefore, to believe that the characteristics of mom's folding proteins may dictate which type of 'tag' will take place in her offspring DNA. It is known that the epigenetic alterations of 'tagging' are regulated by environmental effects. The authors suggest that environmental factors and the mother's lifestyle will thus affect 'tagging' of the offspring DNA, which will dictate how the offspring genes will be utilized. Interestingly, epigenetic changes also take place throughout life depending on the life style of the person.

This article includes the description of altered epigenetic changes which may lead to many types of diseases including metabolic syndrome, cardiovascular disease, autoimmune diseases, neurological disorders, aging and cancer.

The authors proposed another hypothesis which could explain how cancer cells increase copy numbers of tumor promoting genes and decrease or delete tumor inhibiting genes. Sarkar added, "Cancer cells possibly hijack a mechanism operative in normal cells which provides way how the methyl tagged DNA will be untagged by cutting the DNA at the site of tag and repairing it. It is an interesting idea which needs to be tested."

The epigenetic process of 'tagging' that is utilized by living organisms from bacteria to humans is a gold mine for understanding the normal functions of cells and determining where, when, and how these steps deviate from normal behavior to cause disease conditions, a process which is still not well understood.

Epigenetics between the generations

https://www.sciencedaily.com/release...0717100548.htm

We are more than the sum of our genes. Epigenetic mechanisms modulated by environmental cues such as diet, disease or our lifestyle take a major role in regulating the DNA by switching genes on and off. It has been long debated if epigenetic modifications accumulated throughout the entire life can cross the border of generations and be inherited to children or even grand children. Now researchers show robust evidence that not only the inherited DNA itself but also the inherited epigenetic instructions contribute in regulating gene expression in the offspring.

Update 18/07/2017




Unified theory of evolution


https://aeon.co/essays/on-epigenetic...6e0dc-69418129

Update 18/08/2017

[Jo Bowyer]

Transcriptome-Wide Expression Profiling in Skin Fibroblasts of Patients with Joint Hypermobility Syndrome/Ehlers-Danlos Syndrome Hypermobility Type

http://journals.plos.org/plosone/art...l.pone.0161347

Introduction

Ehlers-Danlos syndromes (EDS) are a heterogeneous group of heritable connective tissue disorders (HCTDs) sharing a variable combination of skin hyperextensibility, internal organ and vessel fragility and dysfunctions, and generalized joint hypermobility (gJHM) [1, 2]. Six major EDS types are recognized by specific diagnostic criteria in the Villefranche nosology [3]. Among them, the EDS hypermobility type (EDS-HT, OMIM#130020) is likely the most common [4]. The genetic basis of EDS-HT is still unknown. Hence, EDS-HT is an exclusion diagnosis in presence of gJHM, joint instability complications, smooth, velvety, and/or mildly hyperextensible skin, and positive family history. EDS-HT is considered clinically undistinguishable from the joint hypermobility syndrome (JHS), which was originally recognized by the Brighton criteria [5]. Expert opinion and segregation studies confirm such a clinical impression [6, 7] and the identification of a unified set of diagnostic criteria is underway.

The actual difficulties in recognizing JHS/EDS-HT are due to the low specificity of available diagnostic criteria and the lack of any confirmatory test. Clinical variability is wide and now includes functional gastrointestinal disorders, cardiovascular dysautonomia, and gynecological manifestations, all not comprised in the available diagnostic criteria [8–10]. While tradition defines JHS/EDS-HT as an autosomal dominant trait, incomplete penetrance, variable expressivity and markedly skewed sex ratio lead to hypothesize a much more complex molecular basis for JHS/EDS-HT. The recent identification of a locus on chromosome 8 linked to JHS/EDS-HT in a Belgian multiplex family supports the existence of major Mendelian factors at least in selected families [11]. However, marker locus heterogeneity and complex (i.e., non-Mendelian) inheritance patterns are valid hypotheses that need to be explored in depth.

To gain insights into the pathogenesis of JHS/EDS-HT, we performed a transcriptome-wide expression profiling in five skin fibroblast strains, derived from adult patients with full-blown characteristics and which showed a common disarray of several extracellular matrix (ECM) structural proteins. Our work adds insights into etiopathogenesis of JHS/EDS-HT for future studies aimed at deciphering the molecular basis of such a protean disorder.

[Jo Bowyer]

Genetic and Environmental Risk for Chronic Pain and the Contribution of Risk Variants for Major Depressive Disorder: A Family-Based Mixed-Model Analysis

http://journals.plos.org/plosmedicin...l.pmed.1002090

Abstract

Background

Chronic pain is highly prevalent and a significant source of disability, yet its genetic and environmental risk factors are poorly understood. Its relationship with major depressive disorder (MDD) is of particular importance. We sought to test the contribution of genetic factors and shared and unique environment to risk of chronic pain and its correlation with MDD in Generation Scotland: Scottish Family Health Study (GS:SFHS). We then sought to replicate any significant findings in the United Kingdom Biobank study.

Methods and Findings

Using family-based mixed-model analyses, we examined the contribution of genetics and shared family environment to chronic pain by spouse, sibling, and household relationships. These analyses were conducted in GS:SFHS (n = 23,960), a family- and population-based study of individuals recruited from the Scottish population through their general practitioners. We then examined and partitioned the correlation between chronic pain and MDD and estimated the contribution of genetic factors and shared environment in GS:SFHS. Finally, we used data from two independent genome-wide association studies to test whether chronic pain has a polygenic architecture and examine whether genomic risk of psychiatric disorder predicted chronic pain and whether genomic risk of chronic pain predicted MDD. These analyses were conducted in GS:SFHS and repeated in UK Biobank, a study of 500,000 from the UK population, of whom 112,151 had genotyping and phenotypic data. Chronic pain is a moderately heritable trait (heritability = 38.4%, 95% CI 33.6% to 43.9%) that is significantly concordant in spouses (variance explained 18.7%, 95% CI 9.5% to 25.1%). Chronic pain is positively correlated with depression (ρ = 0.13, 95% CI 0.11 to 0.15, p = 2.72x10-68) and shows a tendency to cluster within families for genetic reasons (genetic correlation = 0.51, 95%CI 0.40 to 0.62, p = 8.24x10-19). Polygenic risk profiles for pain, generated using independent GWAS data, were associated with chronic pain in both GS:SFHS (maximum β = 6.18x10-2, 95% CI 2.84 x10-2 to 9.35 x10-2, p = 4.3x10-4) and UK Biobank (maximum β = 5.68 x 10−2, 95% CI 4.70x10-2 to 6.65x10-2, p < 3x10-4). Genomic risk of MDD is also significantly associated with chronic pain in both GS:SFHS (maximum β = 6.62x10-2, 95% CI 2.82 x10-2 to 9.76 x10-2, p = 4.3x10-4) and UK Biobank (maximum β = 2.56x10-2, 95% CI 1.62x10-2 to 3.63x10-2, p < 3x10-4). Limitations of the current study include the possibility that spouse effects may be due to assortative mating and the relatively small polygenic risk score effect sizes.

Conclusions

Genetic factors, as well as chronic pain in a partner or spouse, contribute substantially to the risk of chronic pain for an individual. Chronic pain is genetically correlated with MDD, has a polygenic architecture, and is associated with polygenic risk of MDD.

Author Summary

Why Was This Study Done?

Genetic factors and the environment you share with your nuclear family, siblings, or spouse may determine your risk of chronic pain.
Depression is also associated with chronic pain, but whether this relationship is explained by shared genetic factors, environment, or both is not known.
We sought to investigate these issues using genetic data and family environmental information from Generation Scotland: Scottish Family Health Study and UK Biobank.

What Did the Researchers Do and Find?

Using data from the family-based Generation Scotland study, we found that genetic factors and the environment you share with your partner/spouse are important risk factors for the development of chronic pain.
Shared genetic and environmental factors also partly explained the association between chronic pain and depression.
Finally, we found evidence showing that the genetic contribution to chronic pain arises through the combined effect of many different genetic risk factors and that the cumulative effects of genetic risk factors for depression increased an individual’s chance of having chronic pain.

What Do These Findings Mean?

Both genetic factors and chronic pain in a partner or spouse contribute to the risk of chronic pain for an individual.
Chronic pain is caused by an accumulation of many small genetic effects and is associated with some of the same genetic and environmental risk factors that confer risk of depression.

[Jo Bowyer]

Evolution of spit

Looking to saliva to gain insight on evolution
https://www.sciencedaily.com/release...0825113228.htm

There's no need to reinvent the genetic wheel. That's one lesson of a new study that looks to the saliva of humans, gorillas, orangutans, macaques and African green monkeys for insights into evolution. The work shows that adaptation isn't just about creating new tools for survival -- it's also about tweaking the ones we have

Recent evolution of the salivary mucin MUC7
http://www.nature.com/articles/srep31791

Duplications, deletions, inversions and translocations of genetic segments, collectively called genomic structural variants, constitute an evolutionarily important form of genetic variants1. When two genomes from the same primate species are compared with each other, structural variants constitute 2 to 7 times more base pair differences than single nucleotide variants2. A functionally relevant, but understudied subset of structural variants, is copy number variation of tandem repeats within individual coding exons (subexonic repeat variation)3. A recent study has shown that, despite the high intrinsic mutability of subexonic repeats, the vast majority of thousands of subexonic repeats remain strongly conserved among mammals4. However, there is no study to our knowledge that specifically investigated the evolution of copy number variable subexonic repeats from their initial emergence as functional units to the adaptive constraints and mutational properties that contributed to their extant variation in primates.

[Jo Bowyer]

The Impact of Endurance Training on Human Skeletal Muscle Memory, Global Isoform Expression and Novel Transcripts

http://journals.plos.org/plosgenetic...l.pgen.1006294

Abstract

Regularly performed endurance training has many beneficial effects on health and skeletal muscle function, and can be used to prevent and treat common diseases e.g. cardiovascular disease, type II diabetes and obesity. The molecular adaptation mechanisms regulating these effects are incompletely understood. To date, global transcriptome changes in skeletal muscles have been studied at the gene level only. Therefore, global isoform expression changes following exercise training in humans are unknown. Also, the effects of repeated interventions on transcriptional memory or training response have not been studied before. In this study, 23 individuals trained one leg for three months. Nine months later, 12 of the same subjects trained both legs in a second training period. Skeletal muscle biopsies were obtained from both legs before and after both training periods. RNA sequencing analysis of all 119 skeletal muscle biopsies showed that training altered the expression of 3,404 gene isoforms, mainly associated with oxidative ATP production. Fifty-four genes had isoforms that changed in opposite directions. Training altered expression of 34 novel transcripts, all with protein-coding potential. After nine months of detraining, no training-induced transcriptome differences were detected between the previously trained and untrained legs. Although there were several differences in the physiological and transcriptional responses to repeated training, no coherent evidence of an endurance training induced transcriptional skeletal muscle memory was found. This human lifestyle intervention induced differential expression of thousands of isoforms and several transcripts from unannotated regions of the genome. It is likely that the observed isoform expression changes reflect adaptational mechanisms and processes that provide the functional and health benefits of regular physical activity.

Author Summary

Skeletal muscle is the most abundant tissue of the healthy human body. It is also highly adaptable to different environmental stimuli, e.g. regular exercise. Exercise training improves overall health and muscle function, and can be used to prevent and treat several common diseases e.g. cardiovascular disease and type II diabetes. Therefore, it is of great importance to understand the molecular mechanisms behind adaptation processes in human skeletal muscle. In this study, we show that different expression variants from the same gene can be regulated in different directions with training, implicating alternative protein functions from one single gene. Such findings are emblematic of the complex mechanisms regulating the effects of training. We also find that training changes the activity of functionally unknown parts of the genome, with the potential for new proteins involved in the health-enhancing effects of exercise. Additionally, our results challenge the belief of a skeletal muscle memory, where previous training can affect the response to a subsequent training period. Overall, we provide understanding of the skeletal muscle biology and novel insights into the mechanisms behind the massive benefits of regular exercise on the human skeletal muscle transcriptome, inspiring further studies for deeper investigation.