A Unique Gene Regulatory Network Resets the Human Germline Epigenome for Development.

Resetting of the epigenome in human primordial germ cells (hPGCs) is critical for development. We show that the transcriptional program of hPGCs is distinct from that in mice, with co-expression of somatic specifiers and naive pluripotency genes TFCP2L1 and KLF4. This unique gene regulatory network, established by SOX17 and BLIMP1, drives comprehensive germline DNA demethylation by repressing DNA methylation pathways and activating TET-mediated hydroxymethylation. Base-resolution methylome analysis reveals progressive DNA demethylation to basal levels in week 5-7 in vivo hPGCs. Concurrently, hPGCs undergo chromatin reorganization, X reactivation, and imprint erasure. Despite global hypomethylation, evolutionarily young and potentially hazardous retroelements, like SVA, remain methylated. Remarkably, some loci associated with metabolic and neurological disorders are also resistant to DNA demethylation, revealing potential for transgenerational epigenetic inheritance that may have phenotypic consequences. We provide comprehensive insight on early human germline transcriptional network and epigenetic reprogramming that subsequently impacts human development and disease.W.C.C.T is supported by Croucher Foundation and Cambridge Trust. P.F.C.is a Wellcome Trust Senior Fellow in Clinical Science (101876/Z/13/Z), and a UK NIHR Senior Investigator with additional support from the Wellcome Trust Centre for Mitochondrial Research (096919Z/11/Z). M.A.S. is supported by HFSP and Wellcome Trust Investigator Award.This is the final version of the article. It first appeared from Elsevier via http://dx.doi.org/10.1016/j.cell.2015.04.05

Dynamical system analysis and forecasting of deformation produced by an earthquake fault

We present a method of constructing low-dimensional nonlinear models describing the main dynamical features of a discrete 2D cellular fault zone, with many degrees of freedom, embedded in a 3D elastic solid. A given fault system is characterized by a set of parameters that describe the dynamics, rheology, property disorder, and fault geometry. Depending on the location in the system parameter space we show that the coarse dynamics of the fault can be confined to an attractor whose dimension is significantly smaller than the space in which the dynamics takes place. Our strategy of system reduction is to search for a few coherent structures that dominate the dynamics and to capture the interaction between these coherent structures. The identification of the basic interacting structures is obtained by applying the Proper Orthogonal Decomposition (POD) to the surface deformations fields that accompany strike-slip faulting accumulated over equal time intervals. We use a feed-forward artificial neural network (ANN) architecture for the identification of the system dynamics projected onto the subspace (model space) spanned by the most energetic coherent structures. The ANN is trained using a standard back-propagation algorithm to predict (map) the values of the observed model state at a future time given the observed model state at the present time. This ANN provides an approximate, large scale, dynamical model for the fault.Comment: 30 pages, 12 figure

Precession of a Freely Rotating Rigid Body. Inelastic Relaxation in the Vicinity of Poles

When a solid body is freely rotating at an angular velocity ${\bf \Omega}$, the ellipsoid of constant angular momentum, in the space $\Omega_1, \Omega_2, \Omega_3$, has poles corresponding to spinning about the minimal-inertia and maximal-inertia axes. The first pole may be considered stable if we neglect the inner dissipation, but becomes unstable if the dissipation is taken into account. This happens because the bodies dissipate energy when they rotate about any axis different from principal. In the case of an oblate symmetrical body, the angular velocity describes a circular cone about the vector of (conserved) angular momentum. In the course of relaxation, the angle of this cone decreases, so that both the angular velocity and the maximal-inertia axis of the body align along the angular momentum. The generic case of an asymmetric body is far more involved. Even the symmetrical prolate body exhibits a sophisticated behaviour, because an infinitesimally small deviation of the body's shape from a rotational symmetry (i.e., a small difference between the largest and second largest moments of inertia) yields libration: the precession trajectory is not a circle but an ellipse. In this article we show that often the most effective internal dissipation takes place at twice the frequency of the body's precession. Applications to precessing asteroids, cosmic-dust alignment, and rotating satellites are discussed.Comment: 47 pages, 1 figur

Digital PCR methods improve detection sensitivity and measurement precision of low abundance mtDNA deletions

Mitochondrial DNA (mtDNA) mutations are a common cause of primary mitochondrial disorders, and have also been implicated in a broad collection of conditions, including aging, neurodegeneration, and cancer. Prevalent among these pathogenic variants are mtDNA deletions, which show a strong bias for the loss of sequence in the major arc between, but not including, the heavy and light strand origins of replication. Because individual mtDNA deletions can accumulate focally, occur with multiple mixed breakpoints, and in the presence of normal mtDNA sequences, methods that detect broad-spectrum mutations with enhanced sensitivity and limited costs have both research and clinical applications. In this study, we evaluated semi-quantitative and digital PCR-based methods of mtDNA deletion detection using double-stranded reference templates or biological samples. Our aim was to describe key experimental assay parameters that will enable the analysis of low levels or small differences in mtDNA deletion load during disease progression, with limited false-positive detection. We determined that the digital PCR method significantly improved mtDNA deletion detection sensitivity through absolute quantitation, improved precision and reduced assay standard error

Exome sequencing in dementia with Lewy bodies.

Dementia with Lewy bodies (DLB) is the second most common form of degenerative dementia. Siblings of affected individuals are at greater risk of developing DLB, but little is known about the underlying genetic basis of the disease. We set out to determine whether mutations in known highly penetrant neurodegenerative disease genes are found in patients with DLB. Whole-exome sequencing was performed on 91 neuropathologically confirmed cases of DLB, supplemented by independent APOE genotyping. Genetic variants were classified using established criteria, and additional neuropathological examination was performed for putative mutation carriers. Likely pathogenic variants previously described as causing monogenic forms of neurodegenerative disease were found in 4.4% of patients with DLB. The APOE ɛ4 allele increased the risk of disease (P=0.0001), conferred a shorter disease duration (P=0.043) and earlier age of death (P=0.0015). In conclusion, although known pathogenic mutations in neurodegenerative disease genes are uncommon in DLB, known genetic risk factors are present in >60% of cases. APOE ɛ4 not only modifies disease risk, but also modulates the rate of disease progression. The reduced penetrance of reported pathogenic alleles explains the lack of a family history in most patients, and the presence of variants previously described as causing frontotemporal dementia suggests a mechanistic overlap between DLB and other neurodegenerative diseases.This study was funded by the NHS National Institute of Health Research Biomedical Research Unit for Lewy body dementia at Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University. Tissue for this study was provided by Newcastle Brain Tissue Resource, which is funded in part by a grant from the UK Medical Research Council and by Brains for Dementia Research, a joint venture between Alzheimer’s Society and Alzheimer’s Research UK. MJK is a Wellcome Trust Clinical Research Training Fellow. PFC is a Wellcome Trust Senior Fellow in Clinical Science and National Institute for Health Research Senior Investigator. He receives funding from the Medical Research Council and the National Institute for Health Research Biomedical Research Centre for Ageing and Age-Related Disease award to the Newcastle upon Tyne Foundation Hospitals National Health Service Trust. The funding sources had no role in study design, data collection/analysis, the writing of the paper or the decision of when or where to publish it. The views expressed here are the views of the authors and not necessarily those of the NHS, NIHR or the Department of Health.This is the final published version. It first appeared at http://www.nature.com/tp/journal/v6/n2/full/tp2015220a.html

Habitual Physical Activity in Mitochondrial Disease

Mitochondrial disease is the most common neuromuscular disease and has a profound impact upon daily life, disease and longevity. Exercise therapy has been shown to improve mitochondrial function in patients with mitochondrial disease. However, no information exists about the level of habitual physical activity of people with mitochondrial disease and its relationship with clinical phenotype.Habitual physical activity, genotype and clinical presentations were assessed in 100 patients with mitochondrial disease. Comparisons were made with a control group individually matched by age, gender and BMI. = −0.49; 95% CI −0.33, −0.63, P<0.01). There were no systematic differences in physical activity between different genotypes mitochondrial disease.These results demonstrate for the first time that low levels of physical activity are prominent in mitochondrial disease. Combined with a high prevalence of obesity, physical activity may constitute a significant and potentially modifiable risk factor in mitochondrial disease

Identification of a novel heterozygous guanosine monophosphate reductase (GMPR) variant in a patient with a late-onset disorder of mitochondrial DNA maintenance

Autosomal dominant progressive external ophthalmoplegia (adPEO) is a late-onset, Mendelian mitochondrial disorder characterised by paresis of the extraocular muscles, ptosis and skeletal-muscle restricted multiple mitochondrial DNA (mtDNA) deletions. While dominantly-inherited, pathogenic variants in POLG, TWNK and RRM2B are among the most common genetic defects of adPEO, identification of novel candidate genes and the underlying pathomechanisms remain challenging. We report the clinical, genetic and molecular investigations of a patient who presented in the seventh decade of life with PEO. Oxidative histochemistry revealed cytochrome c oxidase deficient fibres and occasional ragged red fibres showing subsarcolemmal mitochondrial accumulation in skeletal muscle, while molecular studies identified the presence of multiple mtDNA deletions. Negative candidate screening of known nuclear genes associated with PEO prompted diagnostic exome sequencing, leading to the prioritisation of a novel heterozygous c.547G > C variant in GMPR (NM_006877.3) encoding guanosine monophosphate reductase, a cytosolic enzyme required for maintaining the cellular balance of adenine and guanine nucleotides. We show that the novel c.547G > C variant causes aberrant splicing, decreased GMPR protein levels in patient skeletal muscle, proliferating and quiescent cells and is associated with subtle changes in nucleotide homeostasis protein levels and evidence of disturbed mtDNA maintenance in skeletal muscle. Despite confirmation of GMPR deficiency, demonstrating marked defects of mtDNA replication or nucleotide homeostasis in patient cells proved challenging. Our study proposes that GMPR is the nineteenth (19th) locus for PEO and highlights the complexities of uncovering disease mechanisms in late-onset PEO phenotypes