An integrated map of structural variation in 2,504 human genomes

Structural variants are implicated in numerous diseases and make up the majority of varying nucleotides among human genomes. Here we describe an integrated set of eight structural variant classes comprising both balanced and unbalanced variants, which we constructed using short-read DNA sequencing data and statistically phased onto haplotype blocks in 26 human populations. Analysing this set, we identify numerous gene-intersecting structural variants exhibiting population stratification and describe naturally occurring homozygous gene knockouts that suggest the dispensability of a variety of human genes. We demonstrate that structural variants are enriched on haplotypes identified by genome-wide association studies and exhibit enrichment for expression quantitative trait loci. Additionally, we uncover appreciable levels of structural variant complexity at different scales, including genic loci subject to clusters of repeated rearrangement and complex structural variants with multiple breakpoints likely to have formed through individual mutational events. Our catalogue will enhance future studies into structural variant demography, functional impact and disease association. © 2015 Macmillan Publishers Limited. All rights reserved

Post-traumatic stress and future substance use outcomes: leveraging antecedent factors to stratify risk

Background: Post-traumatic stress disorder (PTSD) and substance use (tobacco, alcohol, and cannabis) are highly comorbid. Many factors affect this relationship, including sociodemographic and psychosocial characteristics, other prior traumas, and physical health. However, few prior studies have investigated this prospectively, examining new substance use and the extent to which a wide range of factors may modify the relationship to PTSD. Methods: The Advancing Understanding of RecOvery afteR traumA (AURORA) study is a prospective cohort of adults presenting at emergency departments (N = 2,943). Participants self-reported PTSD symptoms and the frequency and quantity of tobacco, alcohol, and cannabis use at six total timepoints. We assessed the associations of PTSD and future substance use, lagged by one timepoint, using the Poisson generalized estimating equations. We also stratified by incident and prevalent substance use and generated causal forests to identify the most important effect modifiers of this relationship out of 128 potential variables. Results: At baseline, 37.3% (N = 1,099) of participants reported likely PTSD. PTSD was associated with tobacco frequency (incidence rate ratio (IRR): 1.003, 95% CI: 1.00, 1.01, p = 0.02) and quantity (IRR: 1.01, 95% CI: 1.001, 1.01, p = 0.01), and alcohol frequency (IRR: 1.002, 95% CI: 1.00, 1.004, p = 0.03) and quantity (IRR: 1.003, 95% CI: 1.001, 1.01, p = 0.001), but not with cannabis use. There were slight differences in incident compared to prevalent tobacco frequency and quantity of use; prevalent tobacco frequency and quantity were associated with PTSD symptoms, while incident tobacco frequency and quantity were not. Using causal forests, lifetime worst use of cigarettes, overall self-rated physical health, and prior childhood trauma were major moderators of the relationship between PTSD symptoms and the three substances investigated. Conclusion: PTSD symptoms were highly associated with tobacco and alcohol use, while the association with prospective cannabis use is not clear. Findings suggest that understanding the different risk stratification that occurs can aid in tailoring interventions to populations at greatest risk to best mitigate the comorbidity between PTSD symptoms and future substance use outcomes. We demonstrate that this is particularly salient for tobacco use and, to some extent, alcohol use, while cannabis is less likely to be impacted by PTSD symptoms across the strata

Computational pan-genomics: Status, promises and challenges

Many disciplines, from human genetics and oncology to plant breeding, microbiology and virology, commonly face the challenge of analyzing rapidly increasing numbers of genomes. In case of Homo sapiens, the number of sequenced genomes will approach hundreds of thousands in the next few years. Simply scaling up established bioinformatics pipelines will not be sufficient for leveraging the full potential of such rich genomic data sets. Instead, novel, qualitatively different Computational methods and paradigms are needed.We will witness the rapid extension of Computational pan-genomics, a new sub-area of research in Computational biology. In this article, we generalize existing definitions and understand a pangenome as any collection of genomic sequences to be analyzed jointly or to be used as a reference. We examine already available approaches to construct and use pan-genomes, discuss the potential benefits of future technologies and methodologies and review open challenges from the vantage point of the above-mentioned biological disciplines. As a prominent example for a Computational paradigm shift, we particularly highlight the transition from the representation of reference genomes as strings to representations

Atomic and molecular ejection from ion-bombarded reacted single-crystal surfaces. Oxygen on copper(100)

The trajectories of atomic and molecular species ejected from an ion-bombarded reacted single-crystal surface have been calculated using classical dynamics. As a model system, oxygen has been adsorbed in various coverages and site geometries of the (100) face of a copper surface, which is them bombarded by 600-vY Ar+ ions at normal incidence. The oxygen atoms have been placed at near zero (single-atom adsorption), p(2X2) and c(2X2) coverages in an A-top site, a fourfold bridge site, and a twofold bridge site. From the calculated positions and moments of the ejected adsorbate and substrate atoms, we have identified the important ejection mechanisms, determined relative yields, and determined the factors that influence multimer formation. Of mechanistic interest is that oxygen is most often ejected by collisions with an adjacent copper atom rather than by collisions with the copper atom directly beneath it. The calculation show that multimers of the types Cu(2), CuO, O(2), Cu(2)O, and O(3), and several tetramers and pentamers can be expected to form. These multimers establish their identity over the surface and do not directly eject as a molecular entity. The influence of site geometry on multimer yields is discusses in detail. In general, the bridge sites have higher multimer yields that the A-top site. The surface coverage also exerts a systematic influence on the types of clusters that are observed. For example, molecules like O(2) and CuO(2) are not likely to be ejected from a p(2X2) surface due to a large O-O separation distance.NSF under Grant No. MPS75-9308, and the Materials Research Program under Grant No. DMR-77-23798 and the U.S. Air Force.Approved for public release; distribution is unlimited

Classical trajectory calculations of the energy distribution of ejected atoms from ion bombarded single crystals

The article of record as published may be found at http://dx.doi.org/10.1016/0039-6028(79)90172-9The energy distribution of particles ejected from single crystal surfaces has been calculated using classical dynamics. The model utilizes a microcrystallite of 4 layers with ~60 atoms/layer which is bombarded by 600 eV Ar+ at normal incidence. Calculations have been performed for the clean (100) face of copper as well as for copper with oxygen placed in various coverages and site geometries. The energy distributions for Cu, O, Cu₂, CuO and Cu₃ are reported for this system. The distribution for clean Cu exhibits structure which is shown to arise from preferred ejection mechanisms in the crystal. For oxygen adsorbates, the effect of the oxygen binding energy on the peak in the energy distribution of the ejected oxygen atoms is examined by arbitrarily varying the well-depth of the Cu-O pair potential. In general, higher values of the binding energy produce a maximum in the curve at higher energies and also produce a broader energy distribution. The O₂ and Cu₂ dimer distributions are found to peak at approximately the same energy as the O and Cu curves when compared on a kinetic energy/particle basis, although their widths are considerably smaller. Finally, we predict that the CuO energy distribution should be wider than either the Cu₂ or O₂ distributions since it results from the convolution of the Cu and O distributions which are quite different.National Science FoundationAir Force Office of Scientific Research(CHE78-08728 and DMR/MRL 77-23793)(AF76-2974

Water nanodroplet impacts on surfaces: Effect of the substrate nature

The impact of 1-5 km/s (H2O)n nanodroplets on flat surfaces, with normal or oblique incidence (60°), is modeled using molecular dynamics simulations. The focus is placed on the effect of the substrate, one of the targets being a rigid atomic layer with a repulsive interaction to the droplet, while the other one is a polar surface modeled by three layers of NaCl. In our simulations at 60° incidence, the velocity limit for droplet fragmentation is between 1.5 and 3 km/s for both substrates. However, the dynamics and the energetics of the interaction are very dependent on the substrate nature. While ≤2 km/s droplets glide on the repulsive substrate, keeping most of their translational energy, they stick and stop on the polar substrate, transforming their energy into heat. The influence of the substrate is also pronounced for velocities above the fragmentation threshold, with much higher internal energies and more extensive fragmentation observed for the polar substrate. The results are mainly discussed on the basis of the particle distributions and energy partitions obtained upon interaction. In conclusion, our simulations demonstrate that the nature of the substrate cannot be overlooked in such impact processes. © 2012 Elsevier B.V. All rights reserved

Desorption of large organic molecules induced by keV projectiles

In order to understand the emission of organic molecules in sputtering, classical molecular dynamics (MD) is used to model the 5 keV Ar atom bombardment of polystyrene oligomers adsorbed on Ag{1 1 1}. The analysis of the results shows that a significant fraction of the trajectories generates high action events in the sample. These events are characterized by the simultaneous motion of several hundreds of substrate atoms and, oftentimes, by high emission yields of substrate atoms, clusters and polystyrene molecules. Collision trees representing the energetic part of the cascades confirm that high sputtering yields of molecules occur when a large portion of the primary particle energy is quickly dissipated in the upper layers of the silver substrate. This class of events where high action occurs in the surface region might explain the ejection of organic species with a mass of several kilodaltons such as biomolecules and synthetic polymers. In the simulation, these events are capable of desorbing polystyrene molecules of ∼2 kDa

High yield events of molecule emission induced by keV particle bombardment

In an effort to improve our understanding of large molecule emission in organic SIMS, the sub-kiloelectronvolt and kiloelectronvolt Ar atom-induced sputtering of polystyrene tetramers adsorbed on Ag{111} is modeled using classical molecular dynamics. Above 1 keV, in addition to trajectories consisting of successive collisions between individual atoms, we observe a significant number of high action trajectories where several hundreds of substrate atoms are moving simultaneously. These events can generate unusually high emission yields of substrate atoms, clusters, and polystyrene molecules. Because the probability of high yield events strongly depends on the primary particle energy, representative sets of trajectories are calculated at 150 eV, 500 eV, 1500 eV, and 5 keV. These simulations indicate four main scenarios of action and sputtering. Plots of the energetic parts of the cascade (“collision trees”) show that high sputtering yields occur when most of the primary particle energy is quickly dissipated among silver atoms belonging to the top silver layers. In addition, it is shown that high emission events influence not only the yield but also the kinetic energy distributions of ejected polystyrene molecules. Finally, we discuss the relevance of these high yield mechanisms for the ejection of organic species with a mass of several kilodaltons such as biomolecules and synthetic polymers. Our results show that trajectories falling in the “high yield” category are also capable of desorbing large intact molecules of 2000 Da