Transposable elements (TEs) were first discovered more than 50 years ago, but were totally ignored for a long time. Over the last few decades they have gradually attracted increasing interest from ...research scientists. Initially they were viewed as totally marginal and anecdotic, but TEs have been revealed as potentially harmful parasitic entities, ubiquitous in genomes, and finally as unavoidable actors in the diversity, structure, and evolution of the genome. Since Darwin's theory of evolution, and the progress of molecular biology, transposable elements may be the discovery that has most influenced our vision of (genome) evolution. In this review, we provide a synopsis of what is known about the complex interactions that exist between transposable elements and the host genome. Numerous examples of these interactions are provided, first from the standpoint of the genome, and then from that of the transposable elements. We also explore the evolutionary aspects of TEs in the light of post-Darwinian theories of evolution.
This article was reviewed by Jerzy Jurka, Jürgen Brosius and I. King Jordan. For complete reports, see the Reviewers' reports section.
To efficiently transform genetic associations into drug targets requires evidence that a particular gene, and its encoded protein, contribute causally to a disease. To achieve this, we employ a ...three-step proteome-by-phenome Mendelian Randomization (MR) approach. In step one, 154 protein quantitative trait loci (pQTLs) were identified and independently replicated. From these pQTLs, 64 replicated locally-acting variants were used as instrumental variables for proteome-by-phenome MR across 846 traits (step two). When its assumptions are met, proteome-by-phenome MR, is equivalent to simultaneously running many randomized controlled trials. Step 2 yielded 38 proteins that significantly predicted variation in traits and diseases in 509 instances. Step 3 revealed that amongst the 271 instances from GeneAtlas (UK Biobank), 77 showed little evidence of pleiotropy (HEIDI), and 92 evidence of colocalization (eCAVIAR). Results were wide ranging: including, for example, new evidence for a causal role of tyrosine-protein phosphatase non-receptor type substrate 1 (SHPS1; SIRPA) in schizophrenia, and a new finding that intestinal fatty acid binding protein (FABP2) abundance contributes to the pathogenesis of cardiovascular disease. We also demonstrated confirmatory evidence for the causal role of four further proteins (FGF5, IL6R, LPL, LTA) in cardiovascular disease risk.
Parent-of-origin effects (POE) exist when there is differential expression of alleles inherited from the two parents. A genome-wide scan for POE on DNA methylation at 639,238 CpGs in 5,101 ...individuals identifies 733 independent methylation CpGs potentially influenced by POE at a false discovery rate ≤ 0.05 of which 331 had not previously been identified. Cis and trans methylation quantitative trait loci (mQTL) regulate methylation variation through POE at 54% (399/733) of the identified POE-influenced CpGs. The combined results provide strong evidence for previously unidentified POE-influenced CpGs at 171 independent loci. Methylation variation at 14 of the POE-influenced CpGs is associated with multiple metabolic traits. A phenome-wide association analysis using the POE mQTL SNPs identifies a previously unidentified imprinted locus associated with waist circumference. These results provide a high resolution population-level map for POE on DNA methylation sites, their local and distant regulators and potential consequences for complex traits.
The Generation Scotland: Scottish Family Health Study (GS:SFHS) is a family-based population cohort with DNA, biological samples, socio-demographic, psychological and clinical data from approximately ...24,000 adult volunteers across Scotland. Although data collection was cross-sectional, GS:SFHS became a prospective cohort due to of the ability to link to routine Electronic Health Record (EHR) data. Over 20,000 participants were selected for genotyping using a large genome-wide array.
GS:SFHS was analysed using genome-wide association studies (GWAS) to test the effects of a large spectrum of variants, imputed using the Haplotype Research Consortium (HRC) dataset, on medically relevant traits measured directly or obtained from EHRs. The HRC dataset is the largest available haplotype reference panel for imputation of variants in populations of European ancestry and allows investigation of variants with low minor allele frequencies within the entire GS:SFHS genotyped cohort.
Genome-wide associations were run on 20,032 individuals using both genotyped and HRC imputed data. We present results for a range of well-studied quantitative traits obtained from clinic visits and for serum urate measures obtained from data linkage to EHRs collected by the Scottish National Health Service. Results replicated known associations and additionally reveal novel findings, mainly with rare variants, validating the use of the HRC imputation panel. For example, we identified two new associations with fasting glucose at variants near to Y_RNA and WDR4 and four new associations with heart rate at SNPs within CSMD1 and ASPH, upstream of HTR1F and between PROKR2 and GPCPD1. All were driven by rare variants (minor allele frequencies in the range of 0.08-1%). Proof of principle for use of EHRs was verification of the highly significant association of urate levels with the well-established urate transporter SLC2A9.
GS:SFHS provides genetic data on over 20,000 participants alongside a range of phenotypes as well as linkage to National Health Service laboratory and clinical records. We have shown that the combination of deeper genotype imputation and extended phenotype availability make GS:SFHS an attractive resource to carry out association studies to gain insight into the genetic architecture of complex traits.
Long-term evolution of transposable elements Le Rouzic, Arnaud; Boutin, Thibaud S; Capy, Pierre
Proceedings of the National Academy of Sciences - PNAS,
12/2007, Letnik:
104, Številka:
49
Journal Article
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Transposable elements are often considered parasitic DNA sequences, able to invade the genome of their host thanks to their self-replicating ability. This colonization process has been extensively ...studied, both theoretically and experimentally, but their long-term coevolution with the genomes is still poorly understood. In this work, we aim to challenge previous population genetics models by considering features of transposable elements as quantitative, rather than discrete, variables. We also describe more realistic transposable element dynamics by accounting for the variability of the insertion effect, from deleterious to adaptive, as well as mutations leading to a loss of transposition activity and to nonautonomous copies. Individual-based simulations of the behavior of a transposable-element family over several thousand generations show different ways in which active or inactive copies can be maintained for a very long time. Results reveal an unexpected impact of genetic drift on the "junk DNA" content of the genome and strongly question the likelihood of the sustainable long-term stable transposition-selection equilibrium on which numerous previous works were based.
► Experimental study of micro-single point incremental sheet forming. ► Thin copper sheet. ► Influence of the initial grain size. ► Forming forces measurements. ► Mechanical behavior during ...micro-single point incremental sheet forming process.
Single point incremental forming (SPIF) is a manufacturing process which allows complex shape by the CNC controlled movement of a hemispherical forming tool. The development of thin sheet metal forming processes is limited by the influence of miniaturization at the micro-scale due to size effects. The initial grain size plays a major role on the material behavior at micro-scale.
In this paper, the influence of the initial grain size in micro-SPIF is proposed for thin sheet metals. Tensile tests with different grain sizes have been performed on copper foils. A set of experimental tests of single point incremental sheet forming were conducted on blanks with several grain sizes using two forming strategies. A dedicated material behavior model is proposed and identified. The effects on the forming force evolutions are demonstrated and discussed. An analytical model is also proposed to represent these forces during process in order to set out the tendencies.
Tensile test results revealed that the yield stress, tensile strength and ductility decrease when the ratio of sheet thickness to grain size decreases. Also, the forming forces show an agreement with the results of tensile tests. Remarkably, the decrease in the level of forming forces with respect to the grain size has been demonstrated in relation with the Hall–Petch effect.
The viscoelastic behavior of articular cartilage changes with progression of osteoarthritis. The objective of this study is to quantify this progression and to propose a viscoelastic model of ...articular cartilage taking into account the degree of osteoarthritis that which be easily used in predictive numerical simulations of the hip joint behavior.
To quantify the effects of osteoarthritis (OA) on the viscoelastic behavior of human articular cartilage, samples were obtained from the hip arthroplasty due to femoral neck fracture (normal cartilage) or advanced coxarthrosis (OA cartilage). Experimental data were obtained from instrumented indentation tests on unfrozen femoral cartilage collected and studied in the day following the prosthetic hip surgery pose. By using an inverse method coupled with a numerical modeling (FEM) of all experimental data of the indentation tests, the viscoelastic properties of the two states were quantified.
Mean values of viscoelastic parameters were significantly lower for OA cartilage than normal (instantaneous and relaxed tension moduli, viscosity coefficient). Based on the results and in the thermodynamic framework, a constitutive viscoelastic model taking into account the degree of osteoarthritis as an internal variable of damage is proposed. The isotropic phenomenological viscoelastic model including degradation provides an accurate prediction of the mechanical response of the normal human cartilage and OA cartilage with advanced coxarthrosis but should be further validated for intermediate degrees of osteoarthritis.
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•Viscoelastic behavior of human articular cartilage is identified using indentation.•Effects of osteoarthritis on the viscoelastic behavior is quantified.•A viscoelastic model including degradation is proposed.
The paper is related to the analysis of shape distortions and springback effects arising in single point incremental sheet forming in order to study the use of a FE model based on shell elements to ...perform simulation of the process. A comparison between numerical and experimental results is made to assess the suitability of the model. The measurements of geometrical profile of a truncated cone and springback of cut rings show that the FE model allows to predict accurate results for a set of well defined process parameters. The deformation mechanism of ISF is taken into consideration to determine the limits of the model studied.
Determining toughness properties is crucial for the development of components made of brittle materials, especially at the microscale. Numerous methods rely on establishing a limit load that triggers ...the propagation of a pre-cracked specimen. The primary challenge lies in accurately and repeatably determining this limit load value. In this study, we introduce a coupled numerical-experimental approach to determine the stress intensity factor at the microscale using a micro-bending test on pre-notched cemented carbide micro-cantilevers. Specimens are fabricated through micro-electrical-discharge milling, and the initial crack is generated using a focused ion beam process to ensure a repeatable crack shape. Geometries are defined to validate beam theories.
Cycling bending tests, employing nanoindentation with three types of loading (fatigue-like, progressive repeated, and ramping sinusoidal loadings), are utilized to ascertain fracture toughness properties of tungsten carbide material at the microscale. Micro-indentation is also conducted conventionally to compare hardness at meso and micro-scales. Analytical methods and finite element analysis are employed to extract the critical stress intensity factor. The cyclic bending test with the proposed ramping sinusoidal loading demonstrates a time shift between the applied force and the displacement, enabling accurate and repeatable detection of the initiation of crack propagation. The primary contributions are associated with the development of a micro-bending test on precracked microcantilevers with ramping sinusoidal loading applied by a nanoindentor device. The miniaturization of specimens and tests, for an equivalent grain size, does not result in a scale effect on toughness properties.
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•Micro-cyclic bending test on cemented carbide pre-cracked micro-cantilevers•Extraction of the critical stress intensity factor by coupling numerical and experimental tests at micro scale•Determination of the fracture force by detection of the time shifting between the applied force and the indenter displacement
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