ALBERT

Description: Clonal populations accumulate mutations over time, resulting in different haplotypes. Deep sequencing of such a population in principle provides information to reconstruct these haplotypes and the frequency at which the haplotypes occur. However, this reconstruction is technically not trivial, especially not in clonal systems with a relatively low mutation frequency. The low number of segregating sites in those systems adds ambiguity to the haplotype phasing and thus obviates the reconstruction of genome-wide haplotypes based on sequence overlap information. Therefore, we present EVORhA, a haplotype reconstruction method that complements phasing information in the non-empty read overlap with the frequency estimations of inferred local haplotypes. As was shown with simulated data, as soon as read lengths and/or mutation rates become restrictive for state-of-the-art methods, the use of this additional frequency information allows EVORhA to still reliably reconstruct genome-wide haplotypes. On real data, we show the applicability of the method in reconstructing the population composition of evolved bacterial populations and in decomposing mixed bacterial infections from clinical samples.

Description: Previous formalisms for determining the static perturbation of spherically symmetric self-gravitating elastic Earth models due to displacement dislocations deal with each infinitesimal element of the fault system in its epicentral reference frame. In this work, we overcome this restriction and present novel and compact formulas for obtaining the perturbation due to the whole fault system in an arbitrary and common reference frame. Furthermore, we show that, even in an arbitrary reference frame, it is still possible to discriminate the contributions associated with the polar, bipolar and quadrupolar patterns of the seismic source response, as well as their relation with the along strike, along dip and tensile components of the displacement dislocation. These results allow a better understanding of the relation between the static perturbation and the whole fault system, and find direct applications in geodetic problems, like the modelling of long-wavelength geoid or gravity data from GRACE and GOCE space missions and of the perturbation of the deviatoric inertia tensor of the Earth.

Description: Sensitive instruments like strainmeters and tiltmeters are necessary for measuring slowly varying low amplitude Earth deformations. Nonetheless, laser and fibre interferometers are particularly suitable for interrogating such instruments due to their extreme precision and accuracy. In this paper, a practical design of a simple pendulum borehole tiltmeter based on laser fibre interferometric displacement sensors is presented. A prototype instrument has been constructed using welded borosilicate with a pendulum length of 0.85 m resulting in a main resonance frequency of 0.6 Hz. By implementing three coplanar extrinsic fibre Fabry-Perot interferometric probes and appropriate signal filtering, our instrument provides tilt measurements that are insensitive to parasitic deformations caused by temperature and pressure variations. This prototype has been installed in an underground facility (Rustrel, France) where results show accurate measurements of Earth strains derived from Earth and ocean tides, local hydrologic effects, as well as local and remote earthquakes. The large dynamic range and the high sensitivity of this tiltmeter render it an invaluable tool for numerous geophysical applications such as transient fault motion, volcanic strain and reservoir monitoring.

Description: Data on biological mechanisms of aging are mostly obtained from cross-sectional study designs. An inherent disadvantage of this design is that inter-individual differences can mask small but biologically significant age-dependent changes. A serially sampled design (same individual at different time points) would overcome this problem but is often limited by the relatively small numbers of available paired samples and the statistics being used. To overcome these limitations, we have developed a new vector-based approach, termed three-component analysis, which incorporates temporal distance, signal intensity and variance into one single score for gene ranking and is combined with gene set enrichment analysis. We tested our method on a unique age-based sample set of human skin fibroblasts and combined genome-wide transcription, DNA methylation and histone methylation (H3K4me3 and H3K27me3) data. Importantly, our method can now for the first time demonstrate a clear age-dependent decrease in expression of genes coding for proteins involved in translation and ribosome function. Using analogies with data from lower organisms, we propose a model where age-dependent down-regulation of protein translation-related components contributes to extend human lifespan.

Description: A major challenge in the field of shotgun metagenomics is the accurate identification of organisms present within a microbial community, based on classification of short sequence reads. Though existing microbial community profiling methods have attempted to rapidly classify the millions of reads output from modern sequencers, the combination of incomplete databases, similarity among otherwise divergent genomes, errors and biases in sequencing technologies, and the large volumes of sequencing data required for metagenome sequencing has led to unacceptably high false discovery rates (FDR). Here, we present the application of a novel, gene-independent and signature-based metagenomic taxonomic profiling method with significantly and consistently smaller FDR than any other available method. Our algorithm circumvents false positives using a series of non-redundant signature databases and examines G enomic O rigins T hrough T axonomic CHA llenge (GOTTCHA). GOTTCHA was tested and validated on 20 synthetic and mock datasets ranging in community composition and complexity, was applied successfully to data generated from spiked environmental and clinical samples, and robustly demonstrates superior performance compared with other available tools.

Description: The geocentre motion is the motion of the centre of mass of the entire Earth, considered an isolated system, in a terrestrial system of reference. We first derive a formula relating the harmonic degree-1 Lagrangian variation of the gravity at a station to both the harmonic degree-1 vertical displacement of the station and the displacement of the whole Earth's centre of mass. The relationship is independent of the nature of the Earth deformation and is valid for any source of deformation. We impose no constraint on the system of reference, except that its origin must initially coincide with the centre of mass of the spherically symmetric Earth model. Next, we consider the geocentre motion caused by surface loading. In a system of reference whose origin is the centre of mass of the solid Earth, we obtain a specific relationship between the gravity variation at the surface, the geocentre displacement and the load Love number $h^{\prime }_1$ , which demands the Earth's structure and rheological behaviour be known. For various networks of real or fictitious stations, we invert synthetic signals of surface gravity variations caused by atmospheric loading to retrieve the degree-1 variation of gravity. We then select six well-distributed stations of the Global Geodynamics Project, which is a world network of superconducting gravimeters, to invert actual gravity data for the degree-1 variations and determine the geocentre displacement between the end of 2004 and the beginning of 2012, assuming it to be due to surface loading. We find annual and semi-annual displacements with amplitude 0.5–2.3 mm.

Description: We review the theory of the Earth's elastic and gravitational response to a surface disk load. The solutions for displacement of the surface and the geoid are developed using expansions of Legendre polynomials, their derivatives and the load Love numbers. We provide a matlab  function called diskload that computes the solutions for both uncompensated and compensated disk loads. In order to numerically implement the Legendre expansions, it is necessary to choose a harmonic degree, n max , at which to truncate the series used to construct the solutions. We present a rule of thumb (ROT) for choosing an appropriate value of n max , describe the consequences of truncating the expansions prematurely and provide a means to judiciously violate the ROT when that becomes a practical necessity.

Description: Two types of signals are clearly visible in continuous GPS (cGPS) time-series in Iceland, in particular in the vertical component. The first one is a yearly seasonal cycle, usually sinusoid-like with a minimum in the spring and a maximum in the fall. The second one is a trend of uplift, with higher values the closer the cGPS stations are to the centre of Iceland and ice caps. Here, we study the seasonal cycle signal by deriving its average at 71 GPS sites in Iceland. We estimate the annual and semi-annual components of the cycle in their horizontal and vertical components using a least-squares adjustment. The peak-to-peak amplitude of the cycle of the vertical component at the studied sites ranges from 4 mm near the coastline up to 27 mm at the centre of the Vatnajökull, the largest ice cap in Iceland. The minimum of the seasonal cycle occurs earlier in low lying areas than in the central part of Iceland, consistent with snow load having a large influence on seasonal deformation. Modelling shows that the seasonal cycle is well explained by accounting for elastically induced surface displacements due to snow, atmosphere, reservoir lake and ocean variations. Model displacement fields are derived considering surface loads on a multilayered isotropic spherical Earth. Through forward and inverse modelling, we were able to reproduce a priori information on the average seasonal cycle of known loads (atmosphere, snow in non-glaciated areas and lake reservoir) and get an estimation of other loads (glacier mass balance and ocean). The seasonal glacier mass balance cycle in glaciated areas and snow load in non-glaciated areas are the main contributions to the seasonal deformation. For these loads, induced seasonal vertical displacements range from a few millimetres far from the loads in Iceland, to more than 20 mm at their centres. Lake reservoir load also has to be taken into account on local scale as it can generate up to 20 mm of vertical deformation. Atmosphere load and ocean load are observable and generate vertical displacements in the order of a few millimetres. Inversion results also shows that the Iceland crust is less rigid than the world average. Interannual deviation from the GPS seasonal cycle can occur and are caused by unusual weather conditions over extended period of time.

Description: Chromosome-long haplotyping of human genomes is important to identify genetic variants with differing gene expression, in human evolution studies, clinical diagnosis, and other biological and medical fields. Although several methods have realized haplotyping based on sequencing technologies or population statistics, accuracy and cost are factors that prohibit their wide use. Borrowing ideas from group testing theories, we proposed a clone-based haplotyping method by overlapping pool sequencing. The clones from a single individual were pooled combinatorially and then sequenced. According to the distinct pooling pattern for each clone in the overlapping pool sequencing, alleles for the recovered variants could be assigned to their original clones precisely. Subsequently, the clone sequences could be reconstructed by linking these alleles accordingly and assembling them into haplotypes with high accuracy. To verify the utility of our method, we constructed 130 110 clones in silico for the individual NA12878 and simulated the pooling and sequencing process. Ultimately, 99.9% of variants on chromosome 1 that were covered by clones from both parental chromosomes were recovered correctly, and 112 haplotype contigs were assembled with an N50 length of 3.4 Mb and no switch errors. A comparison with current clone-based haplotyping methods indicated our method was more accurate.

Description: Sexual differentiation of malaria parasites into gametocytes in the vertebrate host and subsequent gamete fertilization in mosquitoes is essential for the spreading of the disease. The molecular processes orchestrating these transitions are far from fully understood. Here, we report the first transcriptome analysis of male and female Plasmodium falciparum gametocytes coupled with a comprehensive proteome analysis. In male gametocytes there is an enrichment of proteins involved in the formation of flagellated gametes; proteins involved in DNA replication, chromatin organization and axoneme formation. On the other hand, female gametocytes are enriched in proteins required for zygote formation and functions after fertilization; protein-, lipid- and energy-metabolism. Integration of transcriptome and proteome data revealed 512 highly expressed maternal transcripts without corresponding protein expression indicating large scale translational repression in P. falciparum female gametocytes for the first time. Despite a high degree of conservation between Plasmodium species, 260 of these ‘repressed transcripts’ have not been previously described. Moreover, for some of these genes, protein expression is only reported in oocysts and sporozoites indicating that repressed transcripts can be partitioned into short- and long-term storage. Finally, these data sets provide an essential resource for identification of vaccine/drug targets and for further mechanistic studies.

Description: DNA methylation is a mechanism for long-term transcriptional regulation and is required for normal cellular differentiation. Failure to properly establish or maintain DNA methylation patterns leads to cell dysfunction and diseases such as cancer. Identifying DNA methylation signatures in complex tissues can be challenging owing to inaccurate cell enrichment methods and low DNA yields. We have developed a technique called laser capture microdissection-reduced representation bisulfite sequencing (LCM-RRBS) for the multiplexed interrogation of the DNA methylation status of cytosine–guanine dinucleotide islands and promoters. LCM-RRBS accurately and reproducibly profiles genome-wide methylation of DNA extracted from microdissected fresh frozen or formalin-fixed paraffin-embedded tissue samples. To demonstrate the utility of LCM-RRBS, we characterized changes in DNA methylation associated with gonadectomy-induced adrenocortical neoplasia in the mouse. Compared with adjacent normal tissue, the adrenocortical tumors showed reproducible gains and losses of DNA methylation at genes involved in cell differentiation and organ development. LCM-RRBS is a rapid, cost-effective, and sensitive technique for analyzing DNA methylation in heterogeneous tissues and will facilitate the investigation of DNA methylation in cancer and organ development.

Description: Data from the Gravity Recovery and Climate Experiment (GRACE) satellite mission can be used to estimate the mass change rate for separate drainage systems (DSs) of the Greenland Ice Sheet (GrIS). One approach to do so is by inversion of the level-2 spherical harmonic data to surface mass changes in predefined regions, or mascons. However, the inversion can be numerically unstable for some individual DSs. This occurs mainly for DSs with a small mass change signal that are located in the interior region of Greenland. In this study, we present a modified mascon inversion approach with an improved implementation of the constraint equations to obtain better estimates for individual DSs. We use separate constraints for mass change variability in the coastal zone, where run-off takes place, and for the ice sheet interior above 2000 m, where mass changes are smaller. A multi-objective optimization approach is used to find optimal prior variances for these two areas based on a simulation model. Correlations between adjacent DSs are suppressed when our optimized prior variances are used, while the mass balance estimates for the combination of the DSs that make up the GrIS above 2000 m are not affected significantly. The resulting mass balance estimates for some DSs in the interior are significantly improved compared to an inversion with a single constraint, as determined by a comparison with mass balance estimates from surface mass balance modelling and discharge measurements. The rate of mass change of the GrIS for the period of January 2003 to December 2012 is found to be –266.1 ± 17.2 Gt yr –1 in the coastal zone and areas below 2000 m, and +8.2 ± 8.6 Gt yr –1 in the interior region.

Description: Measurements of ground deformation can be used to identify and interpret geophysical processes occurring at volcanoes. Most studies rely on a single geodetic technique, or fit a geophysical model to the results of multiple geodetic techniques. Here we present a methodology that combines GPS, Total Station measurements and InSAR into a single reference frame to produce an integrated 3-D geodetic velocity surface without any prior geophysical assumptions. The methodology consists of five steps: design of the network, acquisition and processing of the data, spatial integration of the measurements, time series computation and finally the integration of spatial and temporal measurements. The most significant improvements of this method are (1) the reduction of the required field time, (2) the unambiguous detection of outliers, (3) an increased measurement accuracy and (4) the construction of a 3-D geodetic velocity field. We apply this methodology to ongoing motion on Arenal's western flank. Integration of multiple measurement techniques at Arenal volcano revealed a deformation field that is more complex than that described by individual geodetic techniques, yet remains consistent with previous studies. This approach can be applied to volcano monitoring worldwide and has the potential to be extended to incorporate other geodetic techniques and to study transient deformation.

Description: The advent in high-throughput-sequencing (HTS) technologies has revolutionized conventional biodiversity research by enabling parallel capture of DNA sequences possessing species-level diagnosis. However, polymerase chain reaction (PCR)-based implementation is biased by the efficiency of primer binding across lineages of organisms. A PCR-free HTS approach will alleviate this artefact and significantly improve upon the multi-locus method utilizing full mitogenomes. Here we developed a novel multiplex sequencing and assembly pipeline allowing for simultaneous acquisition of full mitogenomes from pooled animals without DNA enrichment or amplification. By concatenating assemblies from three de novo assemblers, we obtained high-quality mitogenomes for all 49 pooled taxa, with 36 species 〉15 kb and the remaining 〉10 kb, including 20 complete mitogenomes and nearly all protein coding genes (99.6%). The assembly quality was carefully validated with Sanger sequences, reference genomes and conservativeness of protein coding genes across taxa. The new method was effective even for closely related taxa, e.g. three Drosophila spp., demonstrating its broad utility for biodiversity research and mito-phylogenomics. Finally, the in silico simulation showed that by recruiting multiple mito-loci, taxon detection was improved at a fixed sequencing depth. Combined, these results demonstrate the plausibility of a multi-locus mito-metagenomics approach as the next phase of the current single-locus metabarcoding method.

Description: Chromatin modifiers and histone modifications are components of a chromatin-signaling network involved in transcription and its regulation. The interactions between chromatin modifiers and histone modifications are often unknown, are based on the analysis of few genes or are studied in vitro . Here, we apply computational methods to recover interactions between chromatin modifiers and histone modifications from genome-wide ChIP-Seq data. These interactions provide a high-confidence backbone of the chromatin-signaling network. Many recovered interactions have literature support; others provide hypotheses about yet unknown interactions. We experimentally verified two of these predicted interactions, leading to a link between H4K20me1 and members of the Polycomb Repressive Complexes 1 and 2. Our results suggest that our computationally derived interactions are likely to lead to novel biological insights required to establish the connectivity of the chromatin-signaling network involved in transcription and its regulation.

Description: In autumn 2012, the new release 05 (RL05) of monthly geopotencial spherical harmonics Stokes coefficients (SC) from Gravity Recovery and Climate Experiment (GRACE) mission was published. This release reduces the noise in high degree and order SC, but they still need to be filtered. One of the most common filtering processing is the combination of decorrelation and Gaussian filters. Both of them are parameters dependent and must be tuned by the users. Previous studies have analyzed the parameters choice for the RL05 GRACE data for oceanic applications, and for RL04 data for global application. This study updates the latter for RL05 data extending the statistics analysis. The choice of the parameters of the decorrelation filter has been optimized to: (1) balance the noise reduction and the geophysical signal attenuation produced by the filtering process; (2) minimize the differences between GRACE and model-based data and (3) maximize the ratio of variability between continents and oceans. The Gaussian filter has been optimized following the latter criteria. Besides, an anisotropic filter, the fan filter, has been analyzed as an alternative to the Gauss filter, producing better statistics.

Description: With read lengths of currently up to 2 x 300 bp, high throughput and low sequencing costs Illumina's MiSeq is becoming one of the most utilized sequencing platforms worldwide. The platform is manageable and affordable even for smaller labs. This enables quick turnaround on a broad range of applications such as targeted gene sequencing, metagenomics, small genome sequencing and clinical molecular diagnostics. However, Illumina error profiles are still poorly understood and programs are therefore not designed for the idiosyncrasies of Illumina data. A better knowledge of the error patterns is essential for sequence analysis and vital if we are to draw valid conclusions. Studying true genetic variation in a population sample is fundamental for understanding diseases, evolution and origin. We conducted a large study on the error patterns for the MiSeq based on 16S rRNA amplicon sequencing data. We tested state-of-the-art library preparation methods for amplicon sequencing and showed that the library preparation method and the choice of primers are the most significant sources of bias and cause distinct error patterns. Furthermore we tested the efficiency of various error correction strategies and identified quality trimming (Sickle) combined with error correction (BayesHammer) followed by read overlapping (PANDAseq) as the most successful approach, reducing substitution error rates on average by 93%.

Description: RNA-seq is a sensitive and accurate technique to compare steady-state levels of RNA between different cellular states. However, as it does not provide an account of transcriptional activity per se , other technologies are needed to more precisely determine acute transcriptional responses. Here, we have developed an easy, sensitive and accurate novel computational method, iRNA-seq , for genome-wide assessment of transcriptional activity based on analysis of intron coverage from total RNA-seq data. Comparison of the results derived from iRNA-seq analyses with parallel results derived using current methods for genome-wide determination of transcriptional activity, i.e. global run-on (GRO)-seq and RNA polymerase II (RNAPII) ChIP-seq, demonstrate that iRNA-seq provides similar results in terms of number of regulated genes and their fold change. However, unlike the current methods that are all very labor-intensive and demanding in terms of sample material and technologies, iRNA-seq is cheap and easy and requires very little sample material. In conclusion, iRNA-seq offers an attractive novel alternative to current methods for determination of changes in transcriptional activity at a genome-wide level.

Description: The static and transient deformations produced by earthquakes cause density perturbations which, in turn, generate immediate, long-range perturbations of the Earth's gravity field. Here, an analytical solution is derived for gravity perturbations produced by a point double-couple source in homogeneous, infinite, non-self-gravitating elastic media. The solution features transient gravity perturbations that occur at any distance from the source between the rupture onset time and the arrival time of seismic P waves, which are of potential interest for real-time earthquake source studies and early warning. An analytical solution for such prompt gravity perturbations is presented in compact form. We show that it approximates adequately the prompt gravity perturbations generated by strike-slip and dip-slip finite fault ruptures in a half-space obtained by numerical simulations based on the spectral element method. Based on the analytical solution, we estimate that the observability of prompt gravity perturbations within 10 s after rupture onset by current instruments is severely challenged by the background microseism noise but may be achieved by high-precision gravity strainmeters currently under development. Our analytical results facilitate parametric studies of the expected prompt gravity signals that could be recorded by gravity strainmeters.

Description: Seismic waves produced by fault ruptures give rise to gravity perturbations. So far, these perturbations have either been modelled as permanent coseismic gravity change in a half-space or spherical Earth model, or as full time-domain model in infinite space. In this paper, we present the explicit solution of gravity perturbations in time domain produced by a double-couple buried in a homogeneous half-space. This result is especially suited to study gravity perturbations up to a few hundreds of kilometres from the epicentre. It facilitates detailed parametric studies of gravity perturbations from fault rupture, and predicts gravity perturbations of real earthquakes with greatly improved accuracy. The results may serve to develop first designs of gravity-assisted earthquake early-warning systems, made possible by a new generation of ultrasensitive gravity gradiometers, which is currently under development.

Description: Continuous gravimetric observations have been made with three successive generations of superconducting gravimeter over 20 yr at Syowa Station ( $39.6\deg$ E, $69.0\deg$ S), East Antarctica. The third-generation instrument, OSG#058, was installed in January 2010 and was calibrated by an absolute gravimeter during January and February, 2010. The estimated scale factor was –73.823 ± 0.053 μGal V –1 (1 μGal = 10 –8 m s –2 ). The first 5 yr of OSG#058 data from 2010 January 7 to 2015 January 10 were decomposed into tidal waves (M3 to Ssa) and other non-tidal components by applying the Bayesian tidal analysis program BAYTAP. Long-term non-tidal gravity residuals, which were obtained by subtracting annual and 18.6 year tidal waves and the predicted gravity response to the Earth's variable rotation, showed significant correlation with the accumulated snow depth measured at Syowa Station. The greatest correlation occurred when the gravity variations lagged the accumulated snow depth by 21 d. To estimate the gravitational effect of the accumulated snow mass, we inferred a conversion factor of 3.13 ± 0.08 μGal m –1 from this relation. The accumulated snow depth at Syowa Station was found to represent an extensive terrestrial water storage (the snow accumulation) around Syowa Station, which was estimated from the Gravity Recovery and Climate Experiment satellite gravity data. The snow accumulation around Syowa Station was detectable by the superconducting gravimeter.

Description: The new release AIUB-RL02 of monthly gravity models from GRACE GPS and K-Band range-rate data is based on reprocessed satellite orbits referring to the reference frame IGb08. The release is consistent with the IERS2010 conventions. Improvements with respect to its predecessor AIUB-RL01 include the use of reprocessed (RL02) GRACE observations, new atmosphere and ocean dealiasing products (RL05), an upgraded ocean tide model (EOT11A), and the interpolation of shallow ocean tides (admittances). The stochastic parametrization of AIUB-RL02 was adapted to include daily accelerometer scale factors, which drastically reduces spurious signal at the 161 d period in C 20 and at other low degree and order gravity field coefficients. Moreover, the correlation between the noise in the monthly gravity models and solar activity is considerably reduced in the new release. The signal and the noise content of the new AIUB-RL02 monthly gravity fields are studied and calibrated errors are derived from their non-secular and non-seasonal variability. The short-period time-variable signal over the oceans, mostly representing noise, is reduced by 50 per cent with respect to AIUB-RL01. Compared to the official GFZ-RL05a and CSR-RL05 monthly models, the AIUB-RL02 stands out by its low noise at high degrees, a fact emerging from the estimation of seasonal variations for selected river basins and of mass trends in polar regions. Two versions of the monthly AIUB-RL02 gravity models, with spherical harmonics resolution of degree and order 60 and 90, respectively, are available for the time period from March 2003 to March 2014 at the International Center for Global Earth Models or from ftp://ftp.unibe.ch/aiub/GRAVITY/GRACE (last accessed 22 March 2016).

Description: Identifying large-scale structural variation in cancer genomes continues to be a challenge to researchers. Current methods rely on genome alignments based on a reference that can be a poor fit to highly variant and complex tumor genomes. To address this challenge we developed a method that uses available breakpoint information to generate models of structural variations. We use these models as references to align previously unmapped and discordant reads from a genome. By using these models to align unmapped reads, we show that our method can help to identify large-scale variations that have been previously missed.

Description: The relative gravimeter is the primary terrestrial instrument for measuring spatially and temporally varying gravitational fields. The background noise of the instrument—that is, non-linear drift and random tares—typically requires some form of least-squares network adjustment to integrate data collected during a campaign that may take several days to weeks. Here, we present an approach to remove the change in the observed relative-gravity differences caused by hydrologic or other transient processes during a single campaign, so that the adjusted gravity values can be referenced to a single epoch. The conceptual approach is an example of coupled hydrogeophysical inversion, by which a hydrologic model is used to inform and constrain the geophysical forward model. The hydrologic model simulates the spatial variation of the rate of change of gravity as either a linear function of distance from an infiltration source, or using a 3-D numerical groundwater model. The linear function can be included in and solved for as part of the network adjustment. Alternatively, the groundwater model is used to predict the change of gravity at each station through time, from which the accumulated gravity change is calculated and removed from the data prior to the network adjustment. Data from a field experiment conducted at an artificial-recharge facility are used to verify our approach. Maximum gravity change due to hydrology (observed using a superconducting gravimeter) during the relative-gravity field campaigns was up to 2.6 μGal d –1 , each campaign was between 4 and 6 d and one month elapsed between campaigns. The maximum absolute difference in the estimated gravity change between two campaigns, two months apart, using the standard network adjustment method and the new approach, was 5.5 μGal. The maximum gravity change between the same two campaigns was 148 μGal, and spatial variation in gravity change revealed zones of preferential infiltration and areas of relatively high groundwater storage. The accommodation for spatially varying gravity change would be most important for long-duration campaigns, campaigns with very rapid changes in gravity and (or) campaigns where especially precise observed relative-gravity differences are used in the network adjustment.

Description: We document two kinds of traveling ionospheric disturbances, namely, CTIDs (Co-tsunami-Traveling-Ionospheric-disturbances) and ATIDs (Ahead-of-Tsunami-Traveling-Ionospheric-disturbances) related to the Tohoku-Oki tsunami of 2011 March 11. They are referred to the disturbances that remain behind and ahead of the principal tsunami wave front, respectively. We first note their presence in a numerical experiment performed using a simulation code coupling the tsunami, atmosphere and ionosphere. This code uses the tsunami wavefield as an input and simulates acoustic-gravity waves (AGWs) in the atmosphere and TIDs, in the form of total electron content (TEC) disturbance, in the ionosphere. The simulated TEC reveals the excitation of CTIDs (at about 2 TECU) and ATIDs (at about 1 TECU), representing up to 5 per cent disturbance over the ambient electron density, and they arise from the dissipation of AGWs in the thermosphere. A novel outcome is that during the tsunami passage between ~6° and 12° of epicentral distance, strong ATIDs arrive ~20–60 min ahead of the tsunami wave front covering ~3°–10° of distance from the tsunami location. Simulation results are compared with the far-field observations using GNSS satellites and confirm that ATIDs are the first detected TEC maximum, occurring 20–60 min ahead of the tsunami arrival. Our simulation also confirms the presence of largest TEC maximum representing CTIDs, 10–20 min after the first tsunami wave. ATIDs reported in this study have characteristics that can be potentially used for the early warning of the tsunami.

Description: In the present work we illustrate a new local inversion algorithm to retrieve the Moho depth from GOCE (Gravity field and steady-state Ocean Circulation Explorer) gravity field. In details the proposed procedure can be divided into two main steps: the first one consists in recognizing and isolating the different geological provinces in the study area by exploiting information coming from the GOCE global gravity field model. Once the main geological provinces are defined, a function relating the crust density of each province with depth is built and used to reduce the data. The gravitational effects of sediments, topography, bathymetry and upper mantle are also removed. In the second step the residual gravitational field is inverted to retrieve the Moho depth and some information on the crustal density. In particular, the clustering of geological province is performed by means of an automatic Bayesian classification algorithm while the inversion of GOCE residual field is performed by adapting the global algorithm developed in the framework of the GEMMA project to the local scale. The procedure, based on an iterative Wiener filter, allows to compute the Moho depth considering lateral as well as radial variations of crustal density. The algorithm has been applied to the fifth release of GOCE time-wise global gravity field model to infer information on the crustal structure in the Western Balkan area, that is, the region laying between Bulgaria and the Adriatic Sea. This region is one of the most complex and active, from the tectonic point of view, in the whole Europe and it is characterized by the presence of the Alpine-Himalayan orogenic belt, formed by the collision between the African and Eurasian plates, and by the opening of the Pannonian Basin. Results show a good agreement between the obtained geological provinces with the actual knowledge on the region. The resulting Moho depth ranges between about 20 km beneath the Adriatic Sea and 45 km in the Dinarides. Comparisons with available seismic data show differences smaller than 1 km (standard deviation).

Description: Gravity variations associated with Earth's oblateness ( J 2 ) have been observed by satellite laser ranging (SLR) since 1976. The J 2 time-series has been used to measure and help understand many geophysical processes within the Earth system ranging from the mantle to the atmosphere. While post glacial rebound and the Earth climate system are believed to be the primary driving forces of long-term and seasonal J 2 variations, the physical cause of decadal and longer timescale J 2 variations has remained uncertain, although recent evidence indicates that polar ice mass changes are important. In this study, we estimate a variety of climate contributions to J 2 over the period 1979–2010, and find that ice mass variations in Greenland and Antarctica are the dominant cause of observed decadal and longer J 2 variations. Residual variations at periods near 10–11 years may reflect limitations of numerical climate models in estimating mass change variability at long periods, but are also suggestive of potential contribution related to variable solar activity.

Description: Any given human individual carries multiple genetic variants that disrupt protein-coding genes, through structural variation, as well as nucleotide variants and indels. Predicting the phenotypic consequences of a gene disruption remains a significant challenge. Current approaches employ information from a range of biological networks to predict which human genes are haploinsufficient (meaning two copies are required for normal function) or essential (meaning at least one copy is required for viability). Using recently available study gene sets, we show that these approaches are strongly biased towards providing accurate predictions for well-studied genes. By contrast, we derive a haploinsufficiency score from a combination of unbiased large-scale high-throughput datasets, including gene co-expression and genetic variation in over 6000 human exomes. Our approach provides a haploinsufficiency prediction for over twice as many genes currently unassociated with papers listed in Pubmed as three commonly-used approaches, and outperforms these approaches for predicting haploinsufficiency for less-studied genes. We also show that fine-tuning the predictor on a set of well-studied ‘gold standard’ haploinsufficient genes does not improve the prediction for less-studied genes. This new score can readily be used to prioritize gene disruptions resulting from any genetic variant, including copy number variants, indels and single-nucleotide variants.

Description: Interferometric synthetic aperture radar (InSAR) technology provides a valuable tool for obtaining Earth surface deformation and topography at high spatial resolution for crustal deformation studies. Similar to global positioning system (GPS), InSAR measurements are affected by the Earth's ionospheric and tropospheric layers as the electromagnetic signals significantly refract while propagating through the different layers. While GPS signals propagating through the neutral atmosphere are affected primarily by the distribution, pressure and temperature of atmospheric gases, including water vapour, the propagation through the ionosphere is mainly affected by the number of free electrons along the signal path. Here, we present the use of dense regional GPS networks for extracting tropospheric zenith delays and ionospheric total electron content (TEC) maps in order to reduce the noise levels in InSAR images. The results show significant reduction in the root mean square (RMS) values when simultaneously combining the two corrections, both at short time periods where no surface deformation is expected, and at longer periods, where imaging of localized subsidence and fault creep is enhanced.

Description: The main objective of the Gravity Recovery and Climate Experiment (GRACE) Atmospheric and Oceanic De-Aliasing Level-1B product (AOD1B) is the removal of high-frequency non-tidal mass variations due to sub-monthly mass transport in the atmosphere and oceans. Application of AOD1B shall avoid aliasing of these high-frequency signals into monthly gravity models derived from modern gravity missions and shall help to derive consistent orbit solutions for altimetry and Satellite Laser Ranging missions. The AOD1B 6-h series of spherical harmonic coefficients up to degree and order 100 are routinely generated at the German Research Centre for Geoscience and distributed to the GRACE Science Data System and the user community. Inputs for this product are acquired from numerical weather prediction models which are regularly revised and consequently not stable in time. The latest AOD1B release 5 (RL05) is based, as all other releases, on input from ECMWF and does not resolve this problem of discontinuities present in the surface pressure and surface geopotential input data. This might contaminate the gravity field variations derived from atmospheric mass variations. In this paper we present a method to overcome this problem during future AOD1B product generation, as well as two new Level-2 products (GAE and GAF) that, over land, fix a posteriori the two jumps present in the already distributed Level-2 RL05 monthly gravity models which were based on AOD1B RL05. The impact of the proposed correction on the variations and long-term trend of the total mass of the atmosphere and on the ice mass balance over Antarctica and over Greenland is also illustrated. We found that the GAE/GAF-corrected trend of the global atmospheric mass over the GRACE mission lifetime significantly decreased from –0.05 to –0.02 mm yr –1 in terms of geoid height. A considerable effect (33 per cent) was also found in the quadratic term of ice mass loss over Antarctica which results in an acceleration of 3.2 Gt yr –1  yr –1 smaller than without applying this correction.

Description: Meta-analysis of gene expression has enabled numerous insights into biological systems, but current methods have several limitations. We developed a method to perform a meta-analysis using the elastic net, a powerful and versatile approach for classification and regression. To demonstrate the utility of our method, we conducted a meta-analysis of lung cancer gene expression based on publicly available data. Using 629 samples from five data sets, we trained a multinomial classifier to distinguish between four lung cancer subtypes. Our meta-analysis-derived classifier included 58 genes and achieved 91% accuracy on leave-one-study-out cross-validation and on three independent data sets. Our method makes meta-analysis of gene expression more systematic and expands the range of questions that a meta-analysis can be used to address. As the amount of publicly available gene expression data continues to grow, our method will be an effective tool to help distill these data into knowledge.

Description: Previous studies of Earth rotation perturbations due to ice-age loading have predicted a slow secular drift of the rotation axis relative to the surface geography (i.e. true polar wander, TPW) of order of several degrees over the Plio-Pleistocene. It has been argued that this drift and the change in the geographic distribution of solar insolation that it implies may have been responsible for important transitions in ice-age climate, including the termination of ice-age cycles.We use a revised rotational stability theory that incorporates a more accurate treatment of the Earth's background ellipticity to reconsider this issue, and demonstrate that the net displacement of the pole predicted in earlier studies disappears. This more muted polar motion is due to two factors: first, the revised theory no longer predicts the permanent shift in the rotation axis, or the so-called ‘unidirectional TPW’, that appears in the traditional stability theory; and, second, the increased background ellipticity incorporated in the revised predictions acts to reduce the normal mode amplitudes governing the motion of the pole. We conclude that ice-age-induced TPW was not responsible for the termination of the ice age. This does not preclude the possibility that TPW induced by mantle convective flow may have played a role in major Plio-Pleistocene climate transitions, including the onset of Northern Hemisphere glaciation.

Description: Apparent acceleration in Gravity Recovery and Climate Experiment (GRACE) Antarctic ice mass time-series may reflect both ice discharge and surface mass balance contributions. However, a recent study suggests there is also contamination from errors in atmospheric pressure de-aliasing fields [European Center for Medium-Range Weather Forecast (ECMWF) operational products] used during GRACE data processing. To further examine this question, we compare GRACE atmospheric pressure de-aliasing (GAA) fields with in situ surface pressure data from coastal and inland stations. Differences between the two are likely due to GAA errors, and provide a measure of error in GRACE solutions. Time-series of differences at individual weather stations are fit to four presumed error components: annual sinusoids, a linear trend, an acceleration term and jumps at times of known ECMWF model changes. Using data from inland stations, we estimate that atmospheric pressure error causes an acceleration error of about +7.0 Gt yr –2 , which is large relative to prior GRACE estimates of Antarctic ice mass acceleration in the range of –12 to –14 Gt yr –2 . We also estimate apparent acceleration rates from other barometric pressure (reanalysis) fields, including ERA-Interim, MERRA and NCEP/DOE. When integrated over East Antarctica, the four mass acceleration estimates (from GAA and the three reanalysis fields) vary considerably (by ~2–16 Gt yr –2 ). This shows the need for further effort to improve atmospheric mass estimates in this region of sparse in situ observations, in order to use GRACE observations to measure ice mass acceleration and related sea level change.

Description: The long-wavelength gravity field contains information about processes in the sublithospheric mantle. As satellite-derived gravity models now provide the long to medium-wavelength gravity field at unprecedented accuracy, techniques used to process gravity data need to be updated. We show that when determining these long-wavelengths, the treatment of topographic-isostatic effect (TIE) and isostatic effects (IE) is a likely source of error. We constructed a global isostatic model and calculated global TIE and IE. These calculations were done for ground stations as well as stations at satellite height. We considered both gravity and gravity gradients. Using these results, we determined how much of the gravity signal comes from distant sources. We find that a significant long-wavelength bias is introduced if far-field effects on the topographic effect are neglected. However, due to isostatic compensation far-field effects of the topographic effect are to a large degree compensated by the far-field IE. This means that far-field effects can be reduced effectively by always considering topographic masses together with their compensating isostatic masses. We show that to correctly represent the ultra-long wavelengths, a global background model should be used. This is demonstrated both globally and for a continental-scale case area in North America. In the case of regional modelling, where the ultra-long wavelengths are not of prime importance, gravity gradients can be used to help minimize correction errors caused by far-field effects.

Description: Constraining laterally varying structures in planetary interiors is important for understanding both the composition and the internal dynamics of a planet. Recognizing that seismic imaging technique is currently only viable for studying the Earth's interior structures, methods that can be supported by advanced space geodetic techniques may become alternatives to ‘image’ the interiors of other planets. The method of tidal tomography is one possibility, and it relies on high precision measurement of the response of a planet to its body tide. However, it is essential to develop an efficient analytical tool that computes the dependence of tidal response to 3-D interior structures. In this paper, we present a complete formulation of such an analytical tool, which calculates to high accuracy the tidal response of a terrestrial planet with lateral heterogeneities in its elastic and density structures. We treat the lateral heterogeneities as small perturbations and derive the governing equations based on the perturbation theory. In a spherical harmonic representation, equations at each order of perturbation are reduced into multiple matrix equations at harmonics that are allowed by mode couplings, and the total response equals the sum of all those single-harmonic responses, which can be solved semi-analytically. We test our perturbation method by applying it to the Moon with a harmonic degree-1 mantle structure for which the perturbation solutions of the tidal response are compared with those from a fully numerical method. The remarkable agreement between results from these two methods validates the perturbation method. As an example, we then use the perturbation method to evaluate the impact of lunar crustal thickness variations on tidal response of the Moon. We find that lunar crust produces much smaller degree-3 tidal responses than a relatively weak degree-1 structure in the deep lunar mantle. Our calculations show that degree-3 tidal response measurements may hold key constraints on possible degree-1 mantle structure of the Moon, as suggested from previous modelling results.

Description: Seismic data are primarily used in studies of the Earth's lithospheric structure including the Moho geometry. In regions, where seismic data are sparse or completely absent, gravimetric or combined gravimetric-seismic methods could be applied to determine the Moho depth. In this study, we derive and present generalized expressions for solving the Vening Meinesz–Moritz's (VMM) inverse problem of isostasy for a Moho depth determination from gravity and vertical gravity-gradient data. By solving the (non-linear) Fredholm's integral equation of the first kind, the linearized observation equations, which functionally relate the (given) gravity/gravity-gradient data to the (unknown) Moho depth, are derived in the spectral domain. The VMM gravimetric results are validated by using available seismic and gravimetric Moho models. Our results show that the VMM Moho solutions obtained by solving the VMM problem for gravity and gravity-gradient data are almost the same. This finding indicates that in global applications, using the global gravity/gravity-gradient data coverage, the spherical harmonic expressions for the gravimetric forward and inverse modelling yield (theoretically) the same results. Globally, these gravimetric solutions have also a relatively good agreement with the CRUST1.0 and GEMMA GOCE models in terms of their rms Moho differences (4.7 km and 4.1 km, respectively).

Description: Advanced sequencing technologies have generated a plethora of data for many chromatin marks in multiple tissues and cell types, yet there is lack of a generalized tool for optimal utility of those data. A major challenge is to quantitatively model the epigenetic dynamics across both the genome and many cell types for understanding their impacts on differential gene regulation and disease. We introduce IDEAS, an i ntegrative and d iscriminative e pigenome a nnotation s ystem, for jointly characterizing epigenetic landscapes in many cell types and detecting differential regulatory regions. A key distinction between our method and existing state-of-the-art algorithms is that IDEAS integrates epigenomes of many cell types simultaneously in a way that preserves the position-dependent and cell type-specific information at fine scales, thereby greatly improving segmentation accuracy and producing comparable annotations across cell types.

Description: Geophysical techniques are widely used to monitor volcanic unrest. A number of studies have also demonstrated that hydrological processes can produce or trigger geophysical signals. Hydrologically induced gravity signals have previously been recorded by specifically designed gravity surveys as well as, inadvertently, by volcano monitoring studies. Water table corrections of microgravity surveys are commonplace. However, the fluctuations of the water table beneath survey locations are often poorly known, and such a correction fails to account for changes in water-mass storage in the unsaturated zone. Here, we combine 2-D axis-symmetrical numerical fluid-flow models with an axis-symmetric, distributed-mass, gravity calculation to model gravity changes in response to fluctuating hydrological recharge. Flow simulations are based on tropical volcanic settings where high surface permeabilities promote thick unsaturated zones. Our study highlights that mass storage (saturation) changes within the unsaturated zone beneath a survey point can generate recordable gravity changes. We show that for a tropical climate, recharge variations can generate gravity variations of over 150 μGal; although, we demonstrate that for the scenarios investigated here, the probability of recording such large signals is low. Our modelling results indicate that microgravity survey corrections based on water table elevation may result in errors of up to 100 μGal. The effect of inter-annual recharge fluctuations dominate over seasonal cycles which makes prediction and correction of the hydrological contribution more difficult. Spatial hydrogeological heterogeneity can also impact on the accuracy of relative gravity surveys, and can even result in the introduction of additional survey errors. The loading fluctuations associated with saturation variations in the unsaturated zone may also have implications for other geophysical monitoring techniques, such as geodetic monitoring of ground deformation.

Description: A new approach based on energy conservation principle for satellite gravimetry mission has been developed and yields more accurate estimation of in situ geopotential difference observables using K-band ranging (KBR) measurements from the Gravity Recovery and Climate Experiment (GRACE) twin-satellite mission. This new approach preserves more gravity information sensed by KBR range-rate measurements and reduces orbit error as compared to previous energy balance methods. Results from analysis of 11 yr of GRACE data indicated that the resulting geopotential difference estimates agree well with predicted values from official Level 2 solutions: with much higher correlation at 0.9, as compared to 0.5–0.8 reported by previous published energy balance studies. We demonstrate that our approach produced a comparable time-variable gravity solution with the Level 2 solutions. The regional GRACE temporal gravity solutions over Greenland reveals that a substantially higher temporal resolution is achievable at 10-d sampling as compared to the official monthly solutions, but without the compromise of spatial resolution, nor the need to use regularization or post-processing.

Description: Several attempts have been made to obtain a radiographic image inside volcanoes using cosmic-ray muons (muography). Muography is expected to resolve highly heterogeneous density profiles near the surface of volcanoes. However, several prior works have failed to make clear observations due to contamination by background noise. The background contamination leads to an overestimation of the muon flux and consequently a significant underestimation of the density in the target mountains. To investigate the origin of the background noise, we performed a Monte Carlo simulation. The main components of the background noise in muography are found to be low-energy protons, electrons and muons in case of detectors without particle identification and with energy thresholds below 1 GeV. This result was confirmed by comparisons with actual observations of nuclear emulsions. This result will be useful for detector design in future works, and in addition some previous works of muography should be reviewed from the view point of background contamination.

Description: Essential to understanding sea level change and its causes during the last interglacial (LIG) is the quantification of uncertainties. In order to estimate the uncertainties, we develop a statistical framework for the comparison of palaeoclimatic sea level index points and GIA model predictions. For the investigation of uncertainties, as well as to generate better model predictions, we implement a massive ensemble approach by applying a data assimilation scheme based on particle filter methods. The different runs are distinguished through varying ice sheet reconstructions based on oxygen-isotope curves and different parameter selections within the GIA model. This framework has several advantages over earlier work, such as the ability to examine either the contribution of individual observations to the results or the probability of specific input parameters. This exploration of input parameters and data leads to a larger range of estimates than previously published work. We illustrate how the assumptions that enter into the statistical analysis, such as the existence of outliers in the observational database or the initial ice volume history, can introduce large variations to the estimate of the maximum highstand. Thus, caution is required to avoid overinterpreting results. We conclude that there are reasonable doubts whether the data sets previously used in statistical analyses are able to tightly constrain the value of maximum highstand during the LIG.

Description: A 3-D density model of the crust and upper mantle beneath the Karoo basin is presented here. The model is constrained using potential field, borehole and seismic data. Uplift of the basin by the end of the Cretaceous has resulted in an unusually high plateau (〉1000 m) covering a large portion of South Africa. Isostatic studies show the topography is largely compensated by changes in Moho depths (~35 km on-craton and 〉45 km off-craton) and changes in lithospheric mantle densities between the Kaapvaal Craton and surrounding regions (~50 kg m –3 increase from on- to off-craton). This density contrast is determined by inverted satellite gravity and gravity gradient data. The highest topography along the edge of the plateau (〉1200 m) and a strong Bouguer gravity low over Lesotho, however, can only be explained by a buoyant asthenosphere with a density decrease of around 40 kg m –3 .

Description: A method to estimate the rotation change in the orientation of the centre-of-figure (CF) frame caused by earthquakes is proposed for the first time. This method involves using the point dislocation theory based on a spherical, non-rotating, perfectly elastic and isotropic (SNREI) Earth. The rotation change in the orientation is related solely to the toroidal displacements of degree one induced by the vertical dip slip dislocation, and the spheroidal displacements induced by an earthquake have no contribution. The effects of two recent large earthquakes, the 2004 Sumatra and the 2011 Tohoku-Oki, are studied. Results showed that the Sumatra and Tohoku-Oki earthquakes both caused the CF frame to rotate by at least tens of μas (micro-arc-second). Although the visible co-seismic displacements are identified and removed from the coordinate time-series, the rotation change due to the unidentified ones and errors in removal is non-negligible. Therefore, the rotation change in the orientation of the CF frame due to seismic deformation should be taken into account in the future in reference frame and geodesy applications.

Description: A majority of large-scale bacterial genome rearrangements involve mobile genetic elements such as insertion sequence (IS) elements. Here we report novel insertions and excisions of IS elements and recombination between homologous IS elements identified in a large collection of Escherichia coli mutation accumulation lines by analysis of whole genome shotgun sequencing data. Based on 857 identified events (758 IS insertions, 98 recombinations and 1 excision), we estimate that the rate of IS insertion is 3.5 x 10 –4 insertions per genome per generation and the rate of IS homologous recombination is 4.5 x 10 –5 recombinations per genome per generation. These events are mostly contributed by the IS elements IS 1 , IS 2 , IS 5 and IS 186 . Spatial analysis of new insertions suggest that transposition is biased to proximal insertions, and the length spectrum of IS-caused deletions is largely explained by local hopping. For any of the ISs studied there is no region of the circular genome that is favored or disfavored for new insertions but there are notable hotspots for deletions. Some elements have preferences for non-coding sequence or for the beginning and end of coding regions, largely explained by target site motifs. Interestingly, transposition and deletion rates remain constant across the wild-type and 12 mutant E. coli lines, each deficient in a distinct DNA repair pathway. Finally, we characterized the target sites of four IS families, confirming previous results and characterizing a highly specific pattern at IS 186 target-sites, 5'-GGGG(N6/N7)CCCC-3'. We also detected 48 long deletions not involving IS elements.

Description: In this study, we propose an approach for determining the geopotential difference using high-frequency-stability microwave links between satellite and ground station based on Doppler cancellation system. Suppose a satellite and a ground station are equipped with precise optical-atomic clocks (OACs) and oscillators. The ground oscillator emits a signal with frequency f a towards the satellite and the satellite receiver (connected with the satellite oscillator) receives this signal with frequency f b which contains the gravitational frequency shift effect and other signals and noises. After receiving this signal, the satellite oscillator transmits and emits, respectively, two signals with frequencies f b and f c towards the ground station. Via Doppler cancellation technique, the geopotential difference between the satellite and the ground station can be determined based on gravitational frequency shift equation by a combination of these three frequencies. For arbitrary two stations on ground, based on similar procedures as described above, we may determine the geopotential difference between these two stations via a satellite. Our analysis shows that the accuracy can reach 1 m 2 s – 2 based on the clocks’ inaccuracy of about 10 –17 (s s –1 ) level. Since OACs with instability around 10 –18 in several hours and inaccuracy around 10 –18 level have been generated in laboratory, the proposed approach may have prospective applications in geoscience, and especially, based on this approach a unified world height system could be realized with one-centimetre level accuracy in the near future.

Description: Extensive and multi-dimensional data sets generated from recent cancer omics profiling projects have presented new challenges and opportunities for unraveling the complexity of cancer genome landscapes. In particular, distinguishing the unique complement of genes that drive tumorigenesis in each patient from a sea of passenger mutations is necessary for translating the full benefit of cancer genome sequencing into the clinic. We address this need by presenting a data integration framework (OncoIMPACT) to nominate patient-specific driver genes based on their phenotypic impact. Extensive in silico and in vitro validation helped establish OncoIMPACT's robustness, improved precision over competing approaches and verifiable patient and cell line specific predictions (2/2 and 6/7 true positives and negatives, respectively). In particular, we computationally predicted and experimentally validated the gene TRIM24 as a putative novel amplified driver in a melanoma patient. Applying OncoIMPACT to more than 1000 tumor samples, we generated patient-specific driver gene lists in five different cancer types to identify modes of synergistic action. We also provide the first demonstration that computationally derived driver mutation signatures can be overall superior to single gene and gene expression based signatures in enabling patient stratification and prognostication. Source code and executables for OncoIMPACT are freely available from http://sourceforge.net/projects/oncoimpact .

Description: Analysis of rewired upstream subnetworks impacting downstream differential gene expression aids the delineation of evolving molecular mechanisms. Cumulative statistics based on conventional differential correlation are limited for subnetwork rewiring analysis since rewiring is not necessarily equivalent to change in correlation coefficients. Here we present a computational method ChiNet to quantify subnetwork rewiring by statistical heterogeneity that enables detection of potential genotype changes causing altered transcription regulation in evolving organisms. Given a differentially expressed downstream gene set, ChiNet backtracks a rewired upstream subnetwork from a super-network including gene interactions known to occur under various molecular contexts. We benchmarked ChiNet for its high accuracy in distinguishing rewired artificial subnetworks, in silico yeast transcription-metabolic subnetworks, and rewired transcription subnetworks for Candida albicans versus Saccharomyces cerevisiae , against two differential-correlation based subnetwork rewiring approaches. Then, using transcriptome data from tolerant S. cerevisiae strain NRRL Y-50049 and a wild-type intolerant strain, ChiNet identified 44 metabolic pathways affected by rewired transcription subnetworks anchored to major adaptively activated transcription factor genes YAP1 , RPN4 , SFP1 and ROX1 , in response to toxic chemical challenges involved in lignocellulose-to-biofuels conversion. These findings support the use of ChiNet in rewiring analysis of subnetworks where differential interaction patterns resulting from divergent nonlinear dynamics abound.

Description: We interpreted the TRIDENT satellite derived gravity field to provide detailed insights into the spatial distribution of the crustal density structures in the area of the Yellow Sea. We used 3-D forward density modelling for the interpretation that incorporated constraints from existing geological and geophysical information. A gravity stripping method is used to separate out the gravity effects of different geological crustal structures. From this analysis we see that (1) the Gunsan sedimentary basin is isostatically compensated. (2) The satellite-derived Bouguer anomalies ranging from 15 to –30 x 10 –5 m s –2 are linked to basin thicknesses in the Yellow Sea. (3) The calculated Moho depth in the Yellow Sea varies from 27 km beneath the deep sedimentary basin to 34 km in the uplifted zones. (4) Moho depth calculations show two distinct areas, characterized by the deepest Moho depths and the largest crustal thicknesses in the Yellow Sea. The one region extends along the Qianliyan Uplift Zone from Jiaodong to Hongsung while the other area extends from southeastern China to Hongsung in the Korean peninsula. Compared to previous works we suggest that they are the part of the collisions zone between North and South China Blocks extending from China to the Korean peninsula via the Yellow Sea.

Description: Regional refinement of the gravity field models from satellite data using spherical radial base functions (SRBF) is an ill-posed problem. This is mainly due to the regional confinement of the data and the base functions, which leads to severe instabilities in the solutions. Here, this ill-posedness as well as the related regularization process are investigated. We compare three methods for the choice of the regularization parameter, which have been frequently used in gravity modelling. These methods are (1) the variance component estimation (VCE), (2) the generalized cross validation (GCV) and (3) the L-curve criterion. A particular emphasis is put on the impact of the SRBF type on the regularization parameter. To do this, we include two types of SRBF which are often used for regional gravity field modelling. These are the Shannon SRBF or the reproducing kernel and the Spline SRBF. The investigations are performed on two months of the real GOCE ultrasensitive gravity gradients over Central Africa and Amazon. The solutions are validated against a state-of-the-art global gravity solution. We conclude that if a proper regularization method is applied, both SRBF deliver more or less the same accuracy. We show that when the Shannon wavelet is used, the L-curve method gives the best results, while with the Spline kernel, the GCV outperforms the other two methods. Moreover, we observe that the estimated coefficients for the Spline kernel cannot be spatially interpreted. In contrast, the coefficients obtained for the Shannon wavelet reflect the energy of the recovered gravity field with a correlation factor of above 95 per cent. Therefore, when combined with the L-curve method, the Shannon SRBF is advantageous for regional gravity field estimation, since it is one of the simplest band-limited SRBF. In addition, it delivers promising solutions and the estimated coefficients represent the characteristics of the gravity field within the target region.

Description: Ribosome biogenesis, a central and essential cellular process, occurs through sequential association and mutual co-folding of protein–RNA constituents in a well-defined assembly pathway. Here, we construct a network of co-evolving nucleotide/amino acid residues within the ribosome and demonstrate that assembly constraints are strong predictors of co-evolutionary patterns. Predictors of co-evolution include a wide spectrum of structural reconstitution events, such as cooperativity phenomenon, protein-induced rRNA reconstitutions, molecular packing of different rRNA domains, protein–rRNA recognition, etc. A correlation between folding rate of small globular proteins and their topological features is known. We have introduced an analogous topological characteristic for co-evolutionary network of ribosome, which allows us to differentiate between rRNA regions subjected to rapid reconstitutions from those hindered by kinetic traps. Furthermore, co-evolutionary patterns provide a biological basis for deleterious mutation sites and further allow prediction of potential antibiotic targeting sites. Understanding assembly pathways of multicomponent macromolecules remains a key challenge in biophysics. Our study provides a ‘proof of concept’ that directly relates co-evolution to biophysical interactions during multicomponent assembly and suggests predictive power to identify candidates for critical functional interactions as well as for assembly-blocking antibiotic target sites.

Description: This paper describes an alternative acceleration approach for determining GRACE monthly gravity field models. The main differences compared to the traditional acceleration approach can be summarized as: (1) The position errors of GRACE orbits in the functional model are taken into account; (2) The range ambiguity is eliminated via the difference of the range measurements and (3) The mean acceleration equation is formed based on Cowell integration. Using this developed approach, a new time-series of GRACE monthly solution spanning the period January 2003 to December 2010, called Tongji_Acc RL01, has been derived. The annual signals from the Tongji_Acc RL01 time-series agree well with those from the GLDAS model. The performance of Tongji_Acc RL01 shows that this new model is comparable with the RL05 models released by CSR and JPL as well as with the RL05a model released by GFZ.

Description: The emergence of new sequencing technologies has facilitated the use of bacterial whole genome alignments for evolutionary studies and outbreak analyses. These datasets, of increasing size, often include examples of multiple different mechanisms of horizontal sequence transfer resulting in substantial alterations to prokaryotic chromosomes. The impact of these processes demands rapid and flexible approaches able to account for recombination when reconstructing isolates’ recent diversification. Gubbins is an iterative algorithm that uses spatial scanning statistics to identify loci containing elevated densities of base substitutions suggestive of horizontal sequence transfer while concurrently constructing a maximum likelihood phylogeny based on the putative point mutations outside these regions of high sequence diversity. Simulations demonstrate the algorithm generates highly accurate reconstructions under realistically parameterized models of bacterial evolution, and achieves convergence in only a few hours on alignments of hundreds of bacterial genome sequences. Gubbins is appropriate for reconstructing the recent evolutionary history of a variety of haploid genotype alignments, as it makes no assumptions about the underlying mechanism of recombination. The software is freely available for download at github.com/sanger-pathogens/Gubbins , implemented in Python and C and supported on Linux and Mac OS X.

Description: Genomic structural variation (SV), a common hallmark of cancer, has important predictive and therapeutic implications. However, accurately detecting SV using high-throughput sequencing data remains challenging, especially for ‘targeted’ resequencing efforts. This is critically important in the clinical setting where targeted resequencing is frequently being applied to rapidly assess clinically actionable mutations in tumor biopsies in a cost-effective manner. We present BreaKmer, a novel approach that uses a ‘kmer’ strategy to assemble misaligned sequence reads for predicting insertions, deletions, inversions, tandem duplications and translocations at base-pair resolution in targeted resequencing data. Variants are predicted by realigning an assembled consensus sequence created from sequence reads that were abnormally aligned to the reference genome. Using targeted resequencing data from tumor specimens with orthogonally validated SV, non-tumor samples and whole-genome sequencing data, BreaKmer had a 97.4% overall sensitivity for known events and predicted 17 positively validated, novel variants. Relative to four publically available algorithms, BreaKmer detected SV with increased sensitivity and limited calls in non-tumor samples, key features for variant analysis of tumor specimens in both the clinical and research settings.

Description: In this paper, we present a method for incorporating prior geological information into potential field data inversion problem. As opposed to the traditional inverse algorithm, our proposed method takes full advantage of prior geological information as a constraint and thus obtains a new objective function for inversion by adding Lagrangian multipliers and slack variables to the traditional inversion method. These additional parameters can be easily solved during iterations. We used both synthetic and observed data sets to test the stability and validity of the proposed method. Our results using synthetic gravity data show that our new method predicts depth and density anomalies more efficiently and accurately than the traditional inversion method that does not include prior geological constraints. Then using observed gravity data in the Three Gorges area and geological constraint information, we obtained the density distribution of the upper and middle crust in this area thus revealing its geological structure. These results confirm the proposed method's validity and indicate its potential application for magnetism data inversion and exploration of geological structures.

Description: It remains enigmatic how slow slip events (SSEs) interact with other slow seismic events and large distant earthquakes at many subduction zones. Here we model the spatiotemporal slip evolution of the most recent long-term SSE in 2009–2011 in the Bungo Channel region, southwest Japan using GEONET GPS position time-series and a Kalman filter-based, time-dependent slip inversion method. We examine the space-time relationship between the geodetically determined slow slip transient and seismically observed low frequency earthquakes (LFEs) and very-low frequency earthquakes (V-LFEs) near the Nankai trough. We find a strong but distinct temporal correlation between transient slip and LFEs and V-LFEs, suggesting a different relationship to the SSE. We also find the great Tohoku-Oki earthquake appears to disrupt the normal source process of the SSE, probably reflecting large-scale stress redistribution caused by the earthquake. Comparison of the 2009–2011 SSE with others in the same region shows much similarity in slip and moment release, confirming its recurrent nature. Comparison of transient slip with plate coupling shows that slip transients mainly concentrate on the transition zone from strong coupling region to downdip LFEs with transient slip relieving elastic strain accumulation at transitional depth. The less consistent spatial correlation between the long-term SSE and seismic slow earthquakes, and susceptibility of these slow earthquakes to various triggering sources including long-term slow slip, suggests caution in using the seismically determined slow earthquakes as a proxy for slow slip.

Description: Normal mode treatments of the Earth's body tide response were developed in the 1980s to account for the effects of Earth rotation, ellipticity, anelasticity and resonant excitation within the diurnal band. Recent space-geodetic measurements of the Earth's crustal displacement in response to luni-solar tidal forcings have revealed geographical variations that are indicative of aspherical deep mantle structure, thus providing a novel data set for constraining deep mantle elastic and density structure. In light of this, we make use of advances in seismic free oscillation literature to develop a new, generalized normal mode theory for the tidal response within the semi-diurnal and long-period tidal band. Our theory involves a perturbation method that permits an efficient calculation of the impact of aspherical structure on the tidal response. In addition, we introduce a normal mode treatment of anelasticity that is distinct from both earlier work in body tides and the approach adopted in free oscillation seismology. We present several simple numerical applications of the new theory. First, we compute the tidal response of a spherically symmetric, non-rotating, elastic and isotropic Earth model and demonstrate that our predictions match those based on standard Love number theory. Second, we compute perturbations to this response associated with mantle anelasticity and demonstrate that the usual set of seismic modes adopted for this purpose must be augmented by a family of relaxation modes to accurately capture the full effect of anelasticity on the body tide response. Finally, we explore aspherical effects including rotation and we benchmark results from several illustrative case studies of aspherical Earth structure against independent finite-volume numerical calculations of the semi-diurnal body tide response. These tests confirm the accuracy of the normal mode methodology to at least the level of numerical error in the finite-volume predictions. They also demonstrate that full coupling of normal modes, rather than group coupling, is necessary for accurate predictions of the body tide response.

Description: A sequence of large earthquakes occurred along the North Anatolian fault in the 20th century. These earthquakes, including the 1999 Izmit/Düzce earthquakes, generally propagated westward towards the Marmara Sea, defining the Main Marmara fault as a potential seismic gap. It is important to conduct a detailed assessment of the seismic hazards along the main Marmara fault because the megacity Istanbul lies only approximately 10 km north of the eastern segment of the Main Marmara fault, which is referred to as the Princes’ Islands Fault segment (PIF). Here, we study the locking status of this fault segment to evaluate the seismic hazard potential. For the first time, combined ascending and descending Interferometric Synthetic Aperture Radar and Global Positioning System observations were used to investigate the crustal deformation associated with the PIF. After careful corrections of the estimated ground velocity, a deformation pattern relating to fault locking near the Princes’ Islands was identified. The modeling results revealed that the slip rate and locking depth of the fault segment show a clear trade-off, which were estimated as 18.9 ± 7.2 mm yr –1 and 12.1 ± 7.0 km, respectively. With a moment accumulation rate of 1.7 ± 0.4  x  10 17 Nm yr –1 (proportional to the product of slip rate and locking depth), our results imply a build-up of a geodetic moment on the PIF and therefore a potential for earthquake hazards in the vicinity of the Istanbul megacity.

Description: Genetic variants in or near miRNA genes can have profound effects on miRNA expression and targeting. As user-friendly software for the impact prediction of miRNA variants on a large scale is still lacking, we created a tool called miRVaS. miRVaS automates this prediction by annotating the location of the variant relative to functional regions within the miRNA hairpin (seed, mature, loop, hairpin arm, flanks) and by annotating all predicted structural changes within the miRNA due to the variant. In addition, the tool defines the most important region that is predicted to have structural changes and calculates a conservation score that is indicative of the reliability of the structure prediction. The output is presented in a tab-separated file, which enables fast screening, and in an html file, which allows visual comparison between wild-type and variant structures. All separate images are provided for downstream use. Finally, we tested two different approaches on a small test set of published functionally validated genetic variants for their capacity to predict the impact of variants on miRNA expression.

Description: Analysis of RNA-seq data often detects numerous ‘non-co-linear’ (NCL) transcripts, which comprised sequence segments that are topologically inconsistent with their corresponding DNA sequences in the reference genome. However, detection of NCL transcripts involves two major challenges: removal of false positives arising from alignment artifacts and discrimination between different types of NCL transcripts ( trans -spliced, circular or fusion transcripts). Here, we developed a new NCL-transcript-detecting method (‘NCLscan’), which utilized a stepwise alignment strategy to almost completely eliminate false calls (〉98% precision) without sacrificing true positives, enabling NCLscan outperform 18 other publicly-available tools (including fusion- and circular-RNA-detecting tools) in terms of sensitivity and precision, regardless of the generation strategy of simulated dataset, type of intragenic or intergenic NCL event, read depth of coverage, read length or expression level of NCL transcript. With the high accuracy, NCLscan was applied to distinguishing between trans -spliced, circular and fusion transcripts on the basis of poly(A)- and nonpoly(A)-selected RNA-seq data. We showed that circular RNAs were expressed more ubiquitously, more abundantly and less cell type-specifically than trans -spliced and fusion transcripts. Our study thus describes a robust pipeline for the discovery of NCL transcripts, and sheds light on the fundamental biology of these non-canonical RNA events in human transcriptome.

Description: We present a distributed slip model for the 1999 M w 6.3 Chamoli earthquake of north India using interferometric synthetic aperture radar (InSAR) data from both ascending and descending orbits and Bayesian estimation of confidence levels and trade-offs of the model geometry parameters. The results of fault-slip inversion in an elastic half-space show that the earthquake ruptured a $9 _{ - 2.2}^{\circ + 3.4}$ northeast-dipping plane with a maximum slip of ~1 m. The fault plane is located at a depth of ~ $15.9_{ - 3.0}^{ + 1.1}$ km and is ~120 km north of the Main Frontal Thrust, implying that the rupture plane was on the northernmost detachment near the mid-crustal ramp of the Main Himalayan Thrust. The InSAR-determined moment is 3.35 x 10 18 Nm with a shear modulus of 30 GPa, equivalent to M w 6.3, which is smaller than the seismic moment estimates of M w 6.4–6.6. Possible reasons for this discrepancy include the trade-off between moment and depth, uncertainties in seismic moment tensor components for shallow dip-slip earthquakes and the role of earth structure models in the inversions. The released seismic energy from recent earthquakes in the Garhwal region is far less than the accumulated strain energy since the 1803 M s 7.5 earthquake, implying substantial hazard of future great earthquakes.

Description: We use a Bayesian formalism combined with a grid node discretization for the linear inversion of gravimetric data in terms of 3-D density distribution. The forward modelling and the inversion method are derived from seismological inversion techniques in order to facilitate joint inversion or interpretation of density and seismic velocity models. The Bayesian formulation introduces covariance matrices on model parameters to regularize the ill-posed problem and reduce the non-uniqueness of the solution. This formalism favours smooth solutions and allows us to specify a spatial correlation length and to perform inversions at multiple scales. We also extract resolution parameters from the resolution matrix to discuss how well our density models are resolved. This method is applied to the inversion of data from the volcanic island of Basse-Terre in Guadeloupe, Lesser Antilles. A series of synthetic tests are performed to investigate advantages and limitations of the methodology in this context. This study results in the first 3-D density models of the island of Basse-Terre for which we identify: (i) a southward decrease of densities parallel to the migration of volcanic activity within the island, (ii) three dense anomalies beneath Petite Plaine Valley, Beaugendre Valley and the Grande-Découverte-Carmichaël-Soufrière Complex that may reflect the trace of former major volcanic feeding systems, (iii) shallow low-density anomalies in the southern part of Basse-Terre, especially around La Soufrière active volcano, Piton de Bouillante edifice and along the western coast, reflecting the presence of hydrothermal systems and fractured and altered rocks.

Description: We compute the gravimetric factor at the Chandler wobble (CW) frequency using time-series from superconducting gravimeters (SG) longer than a decade. We first individually process the polar motion and data at each individual gravity station to estimate the gravimetric factor amplitude and phase, then we make a global analysis by applying a stacking method to different subsets of up to seven SG stations. The stacking is an efficient way of getting rid of local effects and improving the signal-to-noise ratio of the combined data sets. Using the stacking method, we find a gravimetric factor amplitude and phase of 1.118 ± 0.016 and –0.45 ± 0.66 deg, respectively, which is smaller in amplitude than expected. The sources of error are then carefully considered. For both local and global analyses, the uncertainties on our results are reliably constrained by computing the standard deviation of the estimates of the gravimetric factor amplitude and phase for increasing length of the time-series. Constraints on the CW anelastic dissipation can be set since any departure of the gravimetric factor from its elastic value may provide some insights into the dissipative processes that occur at the CW period. In particular, assuming given rheological models for the Earth's mantle enables us to make the link between the gravimetric factor phase and the CW quality factor.

Description: Analysing independent 1-yr data sets of 10 European superconducting gravimeters (SG) reveals statistically significant temporal variations of M2 tidal parameters. Both common short-term (〈2 yr) and long-term (〉2 yr) features are identified in all SG time-series but one. The averaged variations of the amplitude factor are about 0.2. The path of load vector variations equivalent to the temporal changes of tidal parameters suggests the presence of an 8.85 yr modulation (lunar perigee). The tidal waves having the potential to modulate M2 with this period belong to the 3rd degree constituents. Their amplitude factors turn out to be much closer to body tide model predictions than that of the main 2nd degree M2, which indicates ocean loading for 3rd degree waves to be less prominent than for 2nd degree waves within the M2 group. These two different responses to the loading suggest that the observed modulation is more due to insufficient frequency resolution of limited time-series rather than to time variable loading. Presently, SG gravity time-series are still too short to prove if time variable loading processes are involved too as in case of the annual M2 modulation known to appear for analysis intervals of less than 1 yr. Whatever the variations are caused by, they provide the upper accuracy limit for earth model validation and permit estimating the temporal stability of SG scale factors and assessing the quality of gravity time-series.

Description: A sequence of large earthquakes occurred along the North Anatolian fault in the 20th century. These earthquakes, including the 1999 Izmit/Düzce earthquakes, generally propagated westward towards the Marmara Sea, defining the Main Marmara fault as a potential seismic gap. It is important to conduct a detailed assessment of the seismic hazards along the main Marmara fault because the megacity Istanbul lies only approximately 10 km north of the eastern segment of the Main Marmara fault, which is referred to as the Princes’ Islands Fault segment (PIF). Here, we study the locking status of this fault segment to evaluate the seismic hazard potential. For the first time, combined ascending and descending Interferometric Synthetic Aperture Radar and Global Positioning System observations were used to investigate the crustal deformation associated with the PIF. After careful corrections of the estimated ground velocity, a deformation pattern relating to fault locking near the Princes’ Islands was identified. The modeling results revealed that the slip rate and locking depth of the fault segment show a clear trade-off, which were estimated as 18.9 ± 7.2 mm yr –1 and 12.1 ± 7.0 km, respectively. With a moment accumulation rate of 1.7 ± 0.4  x  10 17 Nm yr –1 (proportional to the product of slip rate and locking depth), our results imply a build-up of a geodetic moment on the PIF and therefore a potential for earthquake hazards in the vicinity of the Istanbul megacity.

Description: Deformation analysis in general and strain analysis in particular using permanent GPS networks require proper analysis of time-series in which all functional effects are taken into consideration and all stochastic effects are captured using an appropriate noise model. This contribution addresses both issues when considering the strain parameters of a GPS network. Estimates of spatial correlation, time correlated noise, and multivariate power spectrum for daily position time-series of the Southern California Integrated GPS Network (SCIGN) stations collected between 1996 and 2011 are obtained. Significant signals with periods of 13.63 d and those related to the GPS draconitic year are identified in these time-series. We aim to assess the effect of a realistic noise model of the series on the uncertainties of the strain parameters including displacements, normal and shear strains, and rotations. For the SCIGN network considered, the following results are highlighted. Contrary to the common belief, the uncertainties of the displacements parameters become smaller when taking a realistic noise model into account. This however was not the case when assessing the noise characteristics of the normal and shear strain, and rotation parameters. The uncertainties increase nearly by a factor of two, in agreement to what is expected. Some of the significant deformation parameters of the white noise model become less significant in case of the realistic noise model.

Description: Crustal vertical deformation (CVD) observed by continuous GPS height time-series can be explained largely by surface loading effects recovered from both Gravity Recover and Climate Experiment (GRACE) and General Circulation Models (GCMs) data. We first show that lower degree CVD spatial spectrum due to the Earth's elastic response to a uniform surface loading plays more important roles than that of high-degree case. We then demonstrate that GRACE data with 300–400 km spatial resolution have the ability to detect 99 per cent power of global and regional CVD in spatial spectrum domain using a global frequency–wavenumber spectrum method. We can just use either GRACE or GCMs 36 degree/order (d/o) spherical harmonic coefficients (SHCs) which correspond to 500 km spatial resolution to acquire more than 90 per cent variance of total CVD modeled by up to 180 d/o SHCs at 98 per cent global gridpoints. Globally, CVD modeled by GRACE loading can explain 72 per cent annual amplitude and 69 per cent variance of GPS observed height time-series, which is better than the GCMs results of 64 per cent for annual amplitude and 41 per cent for variance. Using a three cornered hat method, we also show that the noise level of monthly averaged CVD is about 3 mm for both GPS height time-series and GRACE loading result, while that of GCMs result is only 1.3 mm.

Description: Detecting allelic biases from high-throughput sequencing data requires an approach that maximises sensitivity while minimizing false positives. Here, we present Allelome.PRO, an automated user-friendly bioinformatics pipeline, which uses high-throughput sequencing data from reciprocal crosses of two genetically distinct mouse strains to detect allele-specific expression and chromatin modifications. Allelome.PRO extends approaches used in previous studies that exclusively analyzed imprinted expression to give a complete picture of the ‘allelome’ by automatically categorising the allelic expression of all genes in a given cell type into imprinted, strain-biased, biallelic or non-informative. Allelome.PRO offers increased sensitivity to analyze lowly expressed transcripts, together with a robust false discovery rate empirically calculated from variation in the sequencing data. We used RNA-seq data from mouse embryonic fibroblasts from F1 reciprocal crosses to determine a biologically relevant allelic ratio cutoff, and define for the first time an entire allelome. Furthermore, we show that Allelome.PRO detects differential enrichment of H3K4me3 over promoters from ChIP-seq data validating the RNA-seq results. This approach can be easily extended to analyze histone marks of active enhancers, or transcription factor binding sites and therefore provides a powerful tool to identify candidate cis regulatory elements genome wide.

Description: We present a new method to derive 3-D surface deformation from an integration of interferometric synthetic aperture radar (InSAR) images and Global Navigation Satellite System (GNSS) observations based on Akaike's Bayesian Information Criterion (ABIC), considering relationship between deformations of neighbouring locations. This method avoids interpolated errors by excluding the interpolation of GNSS into the same spatial resolution as InSAR images and harnesses the data sets and the prior smooth constraints of surface deformation objectively and simultaneously by using ABIC, which were inherently unresolved in previous studies. In particular, we define surface roughness measuring smoothing degree to evaluate the performance of the prior constraints and deduce the formula of the covariance for the estimation errors to estimate the uncertainty of modelled solution. We validate this method using synthetic tests and the 2008 M w 7.9 Wenchuan earthquake. We find that the optimal weights associated with ABIC minimum are generally at trade-off locations that balance contributions from InSAR, GNSS data sets and the prior constraints. We use this method to evaluate the influence of the interpolated errors from the Ordinary Kriging algorithm on the derivation of surface deformation. Tests show that the interpolated errors may contribute to biasing very large weights imposed on Kriged GNSS data, suggesting that fixing the relative weights is required in this case. We also make a comparison with SISTEM method, indicating that our method allows obtaining better estimations even with sparse GNSS observations. In addition, this method can be generalized to provide a solution for situations where some types of data sets are lacking and can be exploited further to account for data sets such as the integration of displacements along radar lines and offsets along satellite tracks.

Description: While it has been known for some time that offsets in the time-series of Global Navigation Satellite System (GNSS) position estimates degrade station velocity determinations, the magnitude of the effect has not been clear. Using products of the International GNSS Service (IGS), we assess the impact empirically by injecting progressively larger numbers of artificial offsets and solving for a series of long-term secular GNSS frames. Our results show that the stability of the IGS global frame datum is fairly robust, with significant effects at the formal error level only for the R x (and Y-pole) and R z rotational orientations. On the other hand, station velocity estimates are more seriously affected, especially the vertical component. For the typical IGS station, the mean vertical rate uncertainty is already limited to 0.34 mm yr –1 for the current set of position discontinuities. If the number of breaks doubles, which might occur using newer detection schemes, then that uncertainty will worsen by ~40 per cent to 0.48 mm yr –1 . This error source is generally a more important component of realistic velocity uncertainties than any other, including accounting for temporal correlations in the GNSS data. The only way to improve future GNSS velocity estimates is to severely limit manmade displacements at the tracking stations.

Description: We have extended backwards from 2001 to 1979 the current release 05 (RL05) of the Gravity Recovery and Climate Experiment (GRACE) Atmospheric and Oceanic De-aliasing Level-1B (AOD1B) product and studied the impact of this and a previous release 04 (RL04) of the AOD1B product on precise orbits of five altimetry satellites (ERS-1, ERS-2, TOPEX/Poseidon, Envisat and Jason-1) for the time span 1991–2012, as compared to the case when no AOD1B product is used. We have found that using AOD1B RL05 product reduces root mean square (RMS) fits of satellite laser ranging (SLR) observations by about 1.0–6.4 per cent, 2-d arc overlaps in radial, cross-track and along-track directions by about 1.3–12.0, 0.3–10.0 and 2.0–10.0 per cent, respectively, for various satellites tested, as compared to the case without AOD1B product. Using AOD1B RL05 product instead of RL04 one reduces SLR RMS fits by 0.1–0.7 per cent, 2-d arc overlaps in radial, cross-track and along-track directions by 0.1–0.6, 0.1–1.3 and 0.2–1.2 per cent, respectively, for the satellite orbits tested. The multi-mission crossover analysis shows that the application of an AOD1B product reduces the scatter of radial errors by 0.4–2.8 per cent for the satellite missions studied. At the regions with the most pronounced changes the use of the AOD1B products improves the consistency between the sea level as measured by the TOPEX and ERS-2 missions and by the Jason-1 and Envisat missions by 5 to 10 per cent (globally by about 2 per cent). The results of our study show that extended AOD1B RL05 product performs better than the AOD1B RL04 and improves orbits of altimetry satellites and consistency of sea level products.

Description: Identity by descent (IBD) can be reliably detected for long shared DNA segments, which are found in related individuals. However, many studies contain cohorts of unrelated individuals that share only short IBD segments. New sequencing technologies facilitate identification of short IBD segments through rare variants, which convey more information on IBD than common variants. Current IBD detection methods, however, are not designed to use rare variants for the detection of short IBD segments. Short IBD segments reveal genetic structures at high resolution. Therefore, they can help to improve imputation and phasing, to increase genotyping accuracy for low-coverage sequencing and to increase the power of association studies. Since short IBD segments are further assumed to be old, they can shed light on the evolutionary history of humans. We propose HapFABIA, a computational method that applies biclustering to identify very short IBD segments characterized by rare variants. HapFABIA is designed to detect short IBD segments in genotype data that were obtained from next-generation sequencing, but can also be applied to DNA microarray data. Especially in next-generation sequencing data, HapFABIA exploits rare variants for IBD detection. HapFABIA significantly outperformed competing algorithms at detecting short IBD segments on artificial and simulated data with rare variants. HapFABIA identified 160 588 different short IBD segments characterized by rare variants with a median length of 23 kb (mean 24 kb) in data for chromosome 1 of the 1000 Genomes Project. These short IBD segments contain 752 000 single nucleotide variants (SNVs), which account for 39% of the rare variants and 23.5% of all variants. The vast majority—152 000 IBD segments—are shared by Africans, while only 19 000 and 11 000 are shared by Europeans and Asians, respectively. IBD segments that match the Denisova or the Neandertal genome are found significantly more often in Asians and Europeans but also, in some cases exclusively, in Africans. The lengths of IBD segments and their sharing between continental populations indicate that many short IBD segments from chromosome 1 existed before humans migrated out of Africa. Thus, rare variants that tag these short IBD segments predate human migration from Africa. The software package HapFABIA is available from Bioconductor. All data sets, result files and programs for data simulation, preprocessing and evaluation are supplied at http://www.bioinf.jku.at/research/short-IBD .

Description: Glioma is the most common and fatal primary brain tumour with poor prognosis; however, the functional roles of miRNAs in glioma malignant progression are insufficiently understood. Here, we used an integrated approach to identify miRNA functional targets during glioma malignant progression by combining the paired expression profiles of miRNAs and mRNAs across 160 Chinese glioma patients, and further constructed the functional miRNA–mRNA regulatory network. As a result, most tumour-suppressive miRNAs in glioma progression were newly discovered, whose functions were widely involved in gliomagenesis. Moreover, three miRNA signatures, with different combinations of hub miRNAs (regulations≥30) were constructed, which could independently predict the survival of patients with all gliomas, high-grade glioma and glioblastoma. Our network-based method increased the ability to identify the prognostic biomarkers, when compared with the traditional method and random conditions. Hsa-miR-524-5p and hsa-miR-628-5p, shared by these three signatures, acted as protective factors and their expression decreased gradually during glioma progression. Functional analysis of these miRNA signatures highlighted their critical roles in cell cycle and cell proliferation in glioblastoma malignant progression, especially hsa-miR-524-5p and hsa-miR-628-5p exhibited dominant regulatory activities. Therefore, network-based biomarkers are expected to be more effective and provide deep insights into the molecular mechanism of glioma malignant progression.

Description: A major challenge in cancer genomics is uncovering genes with an active role in tumorigenesis from a potentially large pool of mutated genes across patient samples. Here we focus on the interactions that proteins make with nucleic acids, small molecules, ions and peptides, and show that residues within proteins that are involved in these interactions are more frequently affected by mutations observed in large-scale cancer genomic data than are other residues. We leverage this observation to predict genes that play a functionally important role in cancers by introducing a computational pipeline ( http://canbind.princeton.edu ) for mapping large-scale cancer exome data across patients onto protein structures, and automatically extracting proteins with an enriched number of mutations affecting their nucleic acid, small molecule, ion or peptide binding sites. Using this computational approach, we show that many previously known genes implicated in cancers are enriched in mutations within the binding sites of their encoded proteins. By focusing on functionally relevant portions of proteins—specifically those known to be involved in molecular interactions—our approach is particularly well suited to detect infrequent mutations that may nonetheless be important in cancer, and should aid in expanding our functional understanding of the genomic landscape of cancer.

Description: Genome duplication with hybridization, or allopolyploidization, occurs commonly in plants, and is considered to be a strong force for generating new species. However, genome-wide quantification of homeolog expression ratios was technically hindered because of the high homology between homeologous gene pairs. To quantify the homeolog expression ratio using RNA-seq obtained from polyploids, a new method named HomeoRoq was developed, in which the genomic origin of sequencing reads was estimated using mismatches between the read and each parental genome. To verify this method, we first assembled the two diploid parental genomes of Arabidopsis halleri subsp. gemmifera and Arabidopsis lyrata subsp. petraea ( Arabidopsis petraea subsp. umbrosa ), then generated a synthetic allotetraploid, mimicking the natural allopolyploid Arabidopsis kamchatica . The quantified ratios corresponded well to those obtained by Pyrosequencing. We found that the ratios of homeologs before and after cold stress treatment were highly correlated ( r = 0.870). This highlights the presence of nonstochastic polyploid gene regulation despite previous research identifying stochastic variation in expression. Moreover, our new statistical test incorporating overdispersion identified 226 homeologs (1.11% of 20 369 expressed homeologs) with significant ratio changes, many of which were related to stress responses. HomeoRoq would contribute to the study of the genes responsible for polyploid-specific environmental responses.

Description: The paper in question by Van Camp and co-authors [MVC] challenges previous work showing that ground gravity data arising from hydrology can provide a consistent signal for the comparison with satellite gravity data. The data sets used are similar to those used previously, that is, the gravity field as measured by the GRACE satellites versus ground-based data from superconducting gravimeters (SGs) over the same continental area, in this case Central Europe. One of the main impediments in this paper is the presentation that is frequently confusing and misleading as to what the data analysis really shows, for example, the irregular treatment of annual components that are first subtracted then reappear in the analysis. More importantly, we disagree on specific points. Two calculations are included in our comment to illustrate where we believe that the processing in [MVC] paper is deficient. The first deals with their erroneous treatment of the global hydrology using a truncated spherical harmonic approach which explains almost a factor 2 error in their computation of the loading. The second shows the effect of making the wrong assumption in the GRACE/hydrology/surface gravity comparison by inverting the whole of the hydrology loading for underground stations. We also challenge their claims that empirical orthogonal function techniques cannot be done in the presence of periodic components, and that SG data cannot be corrected for comparisons with GRACE data. The main conclusion of their paper, that there is little coherence between ground gravity stations and this invalidates GRACE comparisons, is therefore questionable. There is nothing in [MVC] that contradicts any of the previous papers that have shown clearly a strong relation between seasonal signals obtained from both ground gravity and GRACE satellite data.

Description: The influence of changes in surface ice-mass redistribution and associated viscoelastic response of the Earth, known as glacial isostatic adjustment (GIA), on the Earth's rotational dynamics has long been known. Equally important is the effect of the changes in the rotational dynamics on the viscoelastic deformation of the Earth. This signal, known as the rotational feedback, or more precisely, the rotational feedback on the sea level equation, has been mathematically described by the sea level equation extended for the term that is proportional to perturbation in the centrifugal potential and the second-degree tidal Love number. The perturbation in the centrifugal force due to changes in the Earth's rotational dynamics enters not only into the sea level equation, but also into the conservation law of linear momentum such that the internal viscoelastic force, the perturbation in the gravitational force and the perturbation in the centrifugal force are in balance. Adding the centrifugal-force perturbation to the linear-momentum balance creates an additional rotational feedback on the viscoelastic deformations of the Earth. We term this feedback mechanism, which is studied in this paper, as the rotational feedback on the linear-momentum balance. We extend both the time-domain method for modelling the GIA response of laterally heterogeneous earth models developed by Martinec and the traditional Laplace-domain method for modelling the GIA-induced rotational response to surface loading by considering the rotational feedback on linear-momentum balance. The correctness of the mathematical extensions of the methods is validated numerically by comparing the polar-motion response to the GIA process and the rotationally induced degree 2 and order 1 spherical harmonic component of the surface vertical displacement and gravity field. We present the difference between the case where the rotational feedback on linear-momentum balance is considered against that where it is not. Numerical simulations show that the resulting difference in radial displacement and sea level change between these situations since the Last Glacial Maximum reaches values of ±25 and ±1.8 m, respectively. Furthermore, the surface deformation pattern is modified by up to 10 per cent in areas of former or ongoing glaciation, but by up to 50 per cent at the bottom of the southern Indian ocean. This also results in the movement of coastlines during the last deglaciation to differ between the two cases due to the difference in the ocean loading, which is seen for instance in the area around Hudson Bay, Canada and along the Chinese, Australian or Argentinian coastlines.

Description: During megathrust earthquakes, great ruptures are accompanied by large scale mass redistribution inside the solid Earth and by ocean mass redistribution due to bathymetry changes. These large scale mass displacements can be detected using the monthly gravity maps of the GRACE satellite mission. In recent years it has become increasingly common to use the long wavelength changes in the Earth's gravity field observed by GRACE to infer seismic source properties for large megathrust earthquakes. An important advantage of space gravimetry is that it is independent from the availability of land for its measurements. This is relevant for observation of megathrust earthquakes, which occur mostly offshore, such as the $M_{\text{w}} \sim 9$ 2004 Sumatra–Andaman, 2010 Maule (Chile) and 2011 Tohoku-Oki (Japan) events. In Broerse et al. , we examined the effect of the presence of an ocean above the rupture on long wavelength gravity changes and showed it to be of the first order. Here we revisit the implementation of an ocean layer through the sea level equation and compare the results with approximated methods that have been used in the literature. One of the simplifications usually lies in the assumption of a globally uniform ocean layer. We show that especially in the case of the 2010 Maule earthquake, due to the closeness of the South American continent, the uniform ocean assumption is not valid and causes errors up to 57 per cent for modelled peak geoid height changes (expressed at a spherical harmonic truncation degree of 40). In addition, we show that when a large amount of slip occurs close to the trench, horizontal motions of the ocean floor play a mayor role in the ocean contribution to gravity changes. Using a slip model of the 2011 Tohoku-Oki earthquake that places the majority of slip close to the surface, the peak value in geoid height change increases by 50 per cent due to horizontal ocean floor motion. Furthermore, we test the influence of the maximum spherical harmonic degree at which the sea level equation is performed for sea level changes occurring along coastlines, which shows to be important for relative sea level changes occurring along the shore. Finally, we demonstrate that ocean floor loading, self-gravitation of water and conservation of water mass are of second order importance for coseismic gravity changes. When GRACE observations are used to determine earthquake parameters such as seismic moment or source depth, the uniform ocean layer method introduces large biases, depending on the location of the rupture with respect to the continent. The same holds for interpreting shallow slip when horizontal motions are not properly accounted for in the ocean contribution. In both cases the depth at which slip occurs will be underestimated.

Description: Long-term volcanic subsidence provides insight into intereruptive processes, which comprise the longest portion of the eruptive cycle. Ground-based geodetic surveys of Medicine Lake Volcano (MLV), northern CA, document subsidence at rates of ~–10 mm yr –1 between 1954 and 2004. The long observation period plus the duration and stable magnitude of this signal presents an ideal opportunity to study long-term volcanic deformation, but this first requires accurate knowledge of the geometry and magnitude of the source. Best-fitting analytical source models to past levelling and GPS data sets show conflicting source parameters—primarily the model depth. To overcome this, we combine multiple tracks of InSAR data, each with a different look angle, to improve upon the spatial resolution of ground-based measurements. We compare the results from InSAR to those of past geodetic studies, extending the geodetic record to 2011 and demonstrating that subsidence at MLV continues at ~–10 mm yr –1 . Using geophysical inversions, we obtain the best-fitting analytical source model—a sill located at 9–10 km depth beneath the caldera. This model geometry is similar to those of past studies, providing a good fit to the high spatial density of InSAR measurements, while accounting for the high ratio of vertical to horizontal deformation derived from InSAR and recorded by existing levelling and GPS data sets. We discuss possible causes of subsidence and show that this model supports the hypothesis that deformation at MLV is driven by tectonic extension, gravitational loading, plus a component of volume loss at depth, most likely due to cooling and crystallization within the intrusive complex that underlies the edifice. Past InSAR surveys at MLV, and throughout the Cascades, are of variable success due to dense vegetation, snow cover and atmospheric artefacts. In this study, we demonstrate how InSAR may be successfully used in this setting by applying a suite of multitemporal analysis methods that account for atmospheric and orbital noise sources. These methods include: a stacking strategy based upon the noise characteristics of each data set; pixelwise rate-map formation (-RATE) and persistent scatterer InSAR (StaMPS).

Description: In the literature, the inverted coseismic slip models from seismological and geodetic data for the 2011 Tohoku-Oki earthquake portray significant discrepancies, in particular regarding the intensity and the distribution of the rupture near the trench. For a megathrust earthquake, it is difficult to discern the slip along the shallow part of the fault from the geodetic data, which are often acquired on land. In this paper, we discuss the uncertainties in the slip distribution inversion using the geodetic data for the 2011 Tohoku earthquake and the Fully Bayesian Inversion method. These uncertainties are due to the prior information regarding the boundary conditions at the edges of the fault, the dip subduction angle and the smoothing operator. Using continuous GPS data from the Japan Island, the results for the rigid and free boundary conditions show that they produce remarkably different slip distributions at shallow depths, with the latter producing a large slip exceeding 30 m near the surface. These results indicate that the smoothing operator (gradient or Laplacian schemes) does not severely affect the slip pattern. To better invert the coseismic slip, we then introduce the ocean bottom GPS (OB-GPS) data, which improve the resolution of the shallow part of the fault. We obtain a near-trench slip greater than 40 m that reaches the Earth's surface, regardless of which boundary condition is used. Additionally, we show that using a mean dip angle for the fault as derived from subduction models is adequate if the goal is to invert for the general features of the slip pattern of this megathrust event.

Description: Methods to interpret personal genome sequences are increasingly required. Here, we report a novel framework (EvoTol) to identify disease-causing genes using patient sequence data from within protein coding-regions. EvoTol quantifies a gene's intolerance to mutation using evolutionary conservation of protein sequences and can incorporate tissue-specific gene expression data. We apply this framework to the analysis of whole-exome sequence data in epilepsy and congenital heart disease, and demonstrate EvoTol's ability to identify known disease-causing genes is unmatched by competing methods. Application of EvoTol to the human interactome revealed networks enriched for genes intolerant to protein sequence variation, informing novel polygenic contributions to human disease.

Description: Detecting in vivo transcription factor (TF) binding is important for understanding gene regulatory circuitries. ChIP-seq is a powerful technique to empirically define TF binding in vivo . However, the multitude of distinct TFs makes genome-wide profiling for them all labor-intensive and costly. Algorithms for in silico prediction of TF binding have been developed, based mostly on histone modification or DNase I hypersensitivity data in conjunction with DNA motif and other genomic features. However, technical limitations of these methods prevent them from being applied broadly, especially in clinical settings. We conducted a comprehensive survey involving multiple cell lines, TFs, and methylation types and found that there are intimate relationships between TF binding and methylation level changes around the binding sites. Exploiting the connection between DNA methylation and TF binding, we proposed a novel supervised learning approach to predict TF–DNA interaction using data from base-resolution whole-genome methylation sequencing experiments. We devised beta-binomial models to characterize methylation data around TF binding sites and the background. Along with other static genomic features, we adopted a random forest framework to predict TF–DNA interaction. After conducting comprehensive tests, we saw that the proposed method accurately predicts TF binding and performs favorably versus competing methods.

Description: In general, observations are normally considered to refer to an epoch in time, however, observations take time. During this time span temporal variations of the observable alias the measurement. Similar phenomenon can be defined in the space domain as well: data treated to refer to a geographical location often contains integrated information of the surroundings. In each case the appropriate signal content can partially be recovered by desmoothing the averaged data. The present study delivers the theoretical foundation of a desmoothing method, and suggests its use on different applications in geodesy. The theoretical formulation of the desmoothing has been derived for 1-D and 2-D signals, the latter is interpreted on a plain and also on a sphere. The presented case studies are less elaborated, but intended to demonstrate the need and usefulness of the desmoothing tool.

Description: Extracting geophysical signals from Global Positioning System (GPS) coordinate time-series is a well-established practice that has led to great insights into how the Earth deforms. Often small discontinuities are found in such time-series and are traceable to either broad-scale deformation (i.e. earthquakes) or discontinuities due to equipment changes and/or failures. Estimating these offsets accurately enables the identification of coseismic deformation estimates in the former case, and the removal of unwanted signals in the latter case which then allows tectonic rates to be estimated more accurately. We develop a method to estimate accurately discontinuities in time series of GPS positions at specified epochs, based on a so-called ‘offset series’. The offset series are obtained by varying the amount of GPS data before and after an event while estimating the offset. Two methods, a mean and a weighted mean method, are then investigated to produce the estimated discontinuity from the offset series. The mean method estimates coseismic offsets without making assumptions about geophysical processes that may be present in the data (i.e. tectonic rate, seasonal variations), whereas the weighted mean method includes estimating coseismic offsets with a model of these processes. We investigate which approach is the most appropriate given certain lengths of available data and noise within the time-series themselves. For the Sumatra–Andaman event, with 4.5 yr of pre-event data, we show that between 2 and 3 yr of post-event data are required to produce accurate offset estimates with the weighted mean method. With less data, the mean method should be used, but the uncertainties of the estimated discontinuity are larger.

Description: Complications arise in the interpretation of gravity fields because of interference from systematic degradations, such as boundary blurring and distortion. The major sources of these degradations are the various systematic errors that inevitably occur during gravity field data acquisition, discretization and geophysical forward modelling. To address this problem, we evaluate deconvolution method that aim to detect the clear horizontal boundaries of anomalous sources by the suppression of systematic errors. A convolution-based multilayer projection model, based on the classical 3-D gravity field forward model, is innovatively derived to model the systematic error degradation. Our deconvolution algorithm is specifically designed based on this multilayer projection model, in which three types of systematic error are defined. The degradations of the different systematic errors are considered in the deconvolution algorithm. As the primary source of degradation, the convolution-based systematic error is the main object of the multilayer projection model. Both the random systematic error and the projection systematic error are shown to form an integral part of the multilayer projection model, and the mixed norm regularization method and the primal-dual optimization method are therefore employed to control these errors and stabilize the deconvolution solution. We herein analyse the parameter identification and convergence of the proposed algorithms, and synthetic and field data sets are both used to illustrate their effectiveness. Additional synthetic examples are specifically designed to analyse the effects of the projection systematic error, which is caused by the uncertainty associated with the estimation of the impulse response function.

Description: Enriching target sequences in sequencing libraries via capture hybridization to bait/probes is an efficient means of leveraging the capabilities of next-generation sequencing for obtaining sequence data from target regions of interest. However, homologous sequences from non-target regions may also be enriched by such methods. Here we investigate the fidelity of capture enrichment for complete mitochondrial DNA (mtDNA) genome sequencing by analyzing sequence data for nuclear copies of mtDNA (NUMTs). Using capture-enriched sequencing data from a mitochondria-free cell line and the parental cell line, and from samples previously sequenced from long-range PCR products, we demonstrate that NUMT alleles are indeed present in capture-enriched sequence data, but at low enough levels to not influence calling the authentic mtDNA genome sequence. However, distinguishing NUMT alleles from true low-level mutations (e.g. heteroplasmy) is more challenging. We develop here a computational method to distinguish NUMT alleles from heteroplasmies, using sequence data from artificial mixtures to optimize the method.

Description: Single nucleotide polymorphisms (SNPs) are increasingly used to tag genetic loci associated with phenotypes such as risk of complex diseases. Technically, this is done genome-wide without prior restriction or knowledge of biological feasibility in scans referred to as genome-wide association studies (GWAS). Depending on the linkage disequilibrium (LD) structure at a particular locus, such tagSNPs may be surrogates for many thousands of other SNPs, and it is difficult to distinguish those that may play a functional role in the phenotype from those simply genetically linked. Because a large proportion of tagSNPs have been identified within non-coding regions of the genome, distinguishing functional from non-functional SNPs has been an even greater challenge. A strategy was recently proposed that prioritizes surrogate SNPs based on non-coding chromatin and epigenomic mapping techniques that have become feasible with the advent of massively parallel sequencing. Here, we introduce an R/Bioconductor software package that enables the identification of candidate functional SNPs by integrating information from tagSNP locations, lists of linked SNPs from the 1000 genomes project and locations of chromatin features which may have functional significance. Availability: FunciSNP is available from Bioconductor (bioconductor.org).

Description: We propose to test if gravimetry can prove useful in discriminating different models of long-term deep crustal processes in the case of the Taiwan mountain belt. We discuss two existing tectonic models that differ in the deep processes proposed to sustain the long-term growth of the orogen. One model assumes underplating of the uppermost Eurasian crust with subduction of the deeper part of the crust into the mantle. The other one suggests the accretion of the whole Eurasian crust above crustal-scale ramps, the lower crust being accreted into the collisional orogen. We compute the temporal gravity changes caused only by long-term rock mass transfers at depth for each of them. We show that the underplating model implies a rate of gravity change of –6 x 10 –2 μGal yr –1 , a value that increases to 2 x 10 –2 μGal yr –1 if crustal subduction is neglected. If the accretion of the whole Eurasian crust occurs, a rate of 7 x 10 –2 μGal yr –1 is obtained. The two models tested differ both in signal amplitude and spatial distribution. The yearly gravity changes expected by long-term deep crustal mass processes in Taiwan are two orders of magnitude below the present-day uncertainty of land-based gravity measurements. Assuming that these annually averaged long-term gravity changes will linearly accumulate with ongoing mountain building, multidecadal time-series are needed to identify comparable rates of gravity change. However, as gravity is sensitive to any mass redistribution, effects of short-term processes such as seismicity and surface mass transfers (erosion, sedimentation, ground-water) may prevent from detecting any long-term deep signal. This study indicates that temporal gravity is not appropriate for deciphering the long-term deep crustal processes involved in the Taiwan mountain belt.

Description: The computation of quasi-static deformation for axisymmetric viscoelastic structures on a gravitating spherical earth is addressed using the spectral element method (SEM). A 2-D spectral element domain is defined with respect to spherical coordinates of radius and angular distance from a pole of symmetry, and 3-D viscoelastic structure is assumed to be azimuthally symmetric with respect to this pole. A point dislocation source that is periodic in azimuth is implemented with a truncated sequence of azimuthal order numbers. Viscoelasticity is limited to linear rheologies and is implemented with the correspondence principle in the Laplace transform domain. This leads to a series of decoupled 2-D problems which are solved with the SEM. Inverse Laplace transform of the independent 2-D solutions leads to the time-domain solution of the 3-D equations of quasi-static equilibrium imposed on a 2-D structure. The numerical procedure is verified through comparison with analytic solutions for finite faults embedded in a laterally homogeneous viscoelastic structure. This methodology is applicable to situations where the predominant structure varies in one horizontal direction, such as a structural contrast across (or parallel to) a long strike-slip fault.

Description: The geodetic rates for the gravity variation and vertical uplift in polar regions subject to past and present-day ice-mass changes (PDIMCs) provide important insight into the rheological structure of the Earth. We provide an update of the rates observed at Ny-Ålesund, Svalbard. To do so, we extract and remove the significant seasonal content from the observations. The rate of gravity variations, derived from absolute and relative gravity measurements, is –1.39 ± 0.11 μGal yr –1 . The rate of vertical displacements is estimated using GPS and tide gauge measurements. We obtain 7.94 ± 0.21 and 8.29 ± 1.60 mm yr –1 , respectively. We compare the extracted signal with that predicted by GLDAS/Noah and ERA-interim hydrology models. We find that the seasonal gravity variations are well-represented by local hydrology changes contained in the ERA-interim model. The phase of seasonal vertical displacements are due to non-local continental hydrology and non-tidal ocean loading. However, a large part of the amplitude of the seasonal vertical displacements remains unexplained. The geodetic rates are used to investigate the asthenosphere viscosity and lithosphere/asthenosphere thicknesses. We first correct the updated geodetic rates for those induced by PDIMCs in Svalbard, using published results, and the sea level change due to the melting of the major ice reservoirs. We show that the latter are at the level of the geodetic rate uncertainties and are responsible for rates of gravity variations and vertical displacements of –0.29 ± 0.03 μGal yr –1 and 1.11 ± 0.10 mm yr –1 , respectively. To account for the late Pleistocene deglaciation, we use the global ice evolution model ICE-3G. The Little Ice Age (LIA) deglaciation in Svalbard is modelled using a disc load model with a simple linear temporal evolution. The geodetic rates at Ny-Ålesund induced by the past deglaciations depend on the viscosity structure of the Earth. We find that viscous relaxation time due to the LIA deglaciation in Svalbard is more than 60 times shorter than that due to the Pleistocene deglaciation. We also find that the response to past and PDIMCs of an Earth model with asthenosphere viscosities ranging between 1.0 and 5.5 x 10 18 Pa s and lithosphere (resp. asthenosphere) thicknesses ranging between 50 and 100 km (resp. 120 and 170 km) can explain the rates derived from geodetic observations.

Description: Reconstructing the evolutionary relationships of species is a major goal in biology. Despite the increasing number of completely sequenced genomes, a large number of phylogenetic projects rely on targeted sequencing and analysis of a relatively small sample of marker genes. The selection of these phylogenetic markers should ideally be based on accurate predictions of their combined, rather than individual, potential to accurately resolve the phylogeny of interest. Here we present and validate a new phylogenomics strategy to efficiently select a minimal set of stable markers able to reconstruct the underlying species phylogeny. In contrast to previous approaches, our methodology does not only rely on the ability of individual genes to reconstruct a known phylogeny, but it also explores the combined power of sets of concatenated genes to accurately infer phylogenetic relationships of species not previously analyzed. We applied our approach to two broad sets of cyanobacterial and ascomycetous fungal species, and provide two minimal sets of six and four genes, respectively, necessary to fully resolve the target phylogenies. This approach paves the way for the informed selection of phylogenetic markers in the effort of reconstructing the tree of life.

Description: The 2 principle and the unbiased predictive risk estimator are used to determine optimal regularization parameters in the context of 3-D focusing gravity inversion with the minimum support stabilizer. At each iteration of the focusing inversion the minimum support stabilizer is determined and then the fidelity term is updated using the standard form transformation. Solution of the resulting Tikhonov functional is found efficiently using the singular value decomposition of the transformed model matrix, which also provides for efficient determination of the updated regularization parameter each step. Experimental 3-D simulations using synthetic data of a dipping dike and a cube anomaly demonstrate that both parameter estimation techniques outperform the Morozov discrepancy principle for determining the regularization parameter. Smaller relative errors of the reconstructed models are obtained with fewer iterations. Data acquired over the Gotvand dam site in the south-west of Iran are used to validate use of the methods for inversion of practical data and provide good estimates of anomalous structures within the subsurface.

Description: Global navigation satellite systems (GNSSs) have revealed that a mega-thrust earthquake that occurs in an island-arc trench system causes post-seismic crustal deformation. Such crustal deformation data have been interpreted by combining three mechanisms: afterslip, poroelastic rebound and viscoelastic relaxation. It is seismologically important to determine the contribution of each mechanism because it provides frictional properties between the plate boundaries and viscosity estimates in the asthenosphere which are necessary to evaluate the stress behaviour during earthquake cycles. However, the observation sites of GNSS are mostly deployed over land and can detect only a small part of the large-scale deformation, which precludes a clear separation of the mechanisms. To extend the spatial coverage of the deformation area, recent studies started to use satellite gravity data that can detect long-wavelength deformations over the ocean. To date, compared with theoretical models for calculating the post-seismic crustal deformation, a few models have been proposed to interpret the corresponding gravity variations. Previous approaches have adopted approximations for the effects of compressibility, sphericity and self-gravitation when computing gravity changes. In this study, a new spectral-finite element approach is presented to consider the effects of material compressibility for Burgers viscoelastic earth model with a laterally heterogeneous viscosity distribution. After the basic principles are explained, it is applied to the 2004 Sumatra–Andaman earthquake. For this event, post-seismic deformation mechanisms are still a controversial topic. Using the developed approach, it is shown that the spatial patterns of gravity change generated by the above three mechanisms clearly differ from one another. A comparison of the theoretical simulation results with the satellite gravity data obtained from the Gravity Recovery and Climate Experiment reveals that both afterslip and viscoelastic relaxation are occurring. Considering the spatial patterns in satellite gravity fields is an effective method for investigating post-seismic deformation mechanisms.

Description: Some of the major geothermal anomalies in central Europe are linked to tectonic structures within the top of crystalline basement, which modify strongly the top of this basement. Their assessment is a major challenge in exploration geophysics. Gravity has been proven to be suitable for the detection of mainly large scale lithological and structural inhomogeneities. Indeed, it is well known and proven by different wells that, for example, in northern Switzerland extended negative anomalies are linked to such structures. Due to depth limitation of wells, there vertical extension is often unknown. In this study, we have investigated the potential of gravity for the geometrical characterization of such basement structures. Our approach consists in the combination of the series of Butterworth filters, geological modelling and best-fitting between observed and computed residual anomalies. In this respect, filters of variable wavelength are applied to observed and computed gravity data. The geological model is discretized into a finite element mesh. Near-surface anomalies and the effect of the sedimentary cover were eliminated using cut-off wavelength of 10 km and geological and seismic information. We analysed the potential of preferential Butterworth filtering in a sensitivity study and applied the above mentioned approach to part of the Swiss molasses basin. Sensitivity analyses reveal that such sets of residual anomalies represents a pseudo-tomography revealing the distribution of different structures with depth. This finding allows for interpreting negative anomalies in terms of 3-D volumes. Best-fitting then permits determination of the most likely 3-D geometries of such basement structures. Our model fits both, geological observations and gravity: among 10 deep boreholes in the studied area, six reach the respective units and confirm our distribution of the negative (and positive) anomalies.

Description: A new analytical method for the computation of a truncated series of solid spherical harmonic coefficients (HCs) from data on a spheroid (i.e. an oblate ellipsoid of revolution) is derived, using a transformation between surface and solid spherical HCs. A two-step procedure is derived to extend this transformation beyond degree and order (d/o) 520. The method is compared to the Hotine–Jekeli transformation in a numerical study based on the EGM2008 global gravity model. Both methods are shown to achieve submicrometre precision in terms of height anomalies for a model to d/o 2239. However, both methods result in spherical harmonic models that are different by up to 7.6 mm in height anomalies and 2.5 mGal in gravity disturbances due to the different coordinate system used. While the Hotine–Jekeli transformation requires the use of an ellipsoidal coordinate system, the new method uses only spherical polar coordinates. The Hotine–Jekeli transformation is numerically more efficient, but the new method can more easily be extended to cases where (a linear combination of) normal derivatives of the function under consideration are given on the surface of the spheroid. It therefore provides a solution to many types of ellipsoidal boundary-value problems in the spectral domain.

Description: Visualization of chromosomal dynamics is important for understanding many fundamental intra-nuclear processes. Efficient and reliable live-cell multicolor labeling of chromosomal loci can realize this goal. However, the current methods are constrained mainly by insufficient labeling throughput, efficiency, flexibility as well as photostability. Here we have developed a new approach to realize dual-color chromosomal loci imaging based on a modified single-guide RNA (sgRNA) of the CRISPR/Cas9 system. The modification of sgRNA was optimized by structure-guided engineering of the original sgRNA, consisting of RNA aptamer insertions that bind fluorescent protein-tagged effectors. By labeling and tracking telomeres, centromeres and genomic loci, we demonstrate that the new approach is easy to implement and enables robust dual-color imaging of genomic elements. Importantly, our data also indicate that the fast exchange rate of RNA aptamer binding effectors makes our sgRNA-based labeling method much more tolerant to photobleaching than the Cas9-based labeling method. This is crucial for continuous, long-term tracking of chromosomal dynamics. Lastly, as our method is complementary to other live-cell genomic labeling systems, it is therefore possible to combine them into a plentiful palette for the study of native chromatin organization and genome ultrastructure dynamics in living cells.

Description: We explore Earth's elastic deformation response to ocean tidal loading (OTL) using kinematic Global Positioning System (GPS) observations and forward-modelled predictions across South America. Harmonic coefficients are extracted from up to 14 yr of GPS-inferred receiver locations, which we estimate at 5 min intervals using precise point positioning. We compare the observed OTL-induced surface displacements against predictions derived from spherically symmetric, non-rotating, elastic and isotropic (SNREI) Earth models. We also compare sets of modelled predictions directly for various ocean-tide and Earth-model combinations. The vector differences between predicted displacements computed using separate ocean-tide models reveal uniform-displacement components common to all stations in the South America network. Removal of the network-mean OTL-induced displacements from each site substantially reduces the vector differences between observed and predicted displacements. We focus on the dominant astronomical tidal harmonics from three distinct frequency bands: semidiurnal (M 2 ), diurnal (O 1 ) and fortnightly (M f ). In each band, the observed OTL-induced surface displacements strongly resemble the modelled displacement-response patterns, and the residuals agree to about 0.3 mm or better. Even with the submillimetre correspondence between observations and predictions, we detect regional-scale spatial coherency in the final set of residuals, most notably for the M 2 harmonic. The spatial coherency appears relatively insensitive to the specific choice of ocean-tide or SNREI-Earth model. Varying the load model or 1-D elastic structure yields predicted OTL-induced displacement differences of order 0.1 mm or less for the network. Furthermore, estimates of the observational uncertainty place the noise level below the magnitude of the residual displacements for most stations, supporting our interpretation that random errors cannot account for the entire misfit. Therefore, the spatially coherent residuals may reveal deficiencies in the a priori SNREI Earth models. In particular, the residuals may indicate sensitivity to regional deviations from standard globally averaged Earth structure due to the presence of the South American craton.

Description: Planar faults are widely adopted during inversions to determine slip distributions and fault geometries using geodetic observations; however, little research has been conducted with respect to curved faults. We attribute this to the lack of an appropriate parameterized modelling method. In this paper, we present a curved-fault modelling method (CFMM) that describes a curved fault according to specific parameters, and we also develop a corresponding hybrid iterative inversion algorithm (HIIA) to perform inversions for parametric curved-fault geometries and slips. The results of the strike-component and dip-component synthetic tests show that a complex S-shaped fault surface and a circular slip distribution are successfully recovered, indicating the strong performance of the CFMM and HIIA methods. In addition, we describe and verify a scenario for determining the number of necessary geometrical parameters for the HIIA and examine the case study of the Wenchuan earthquake, which occurred on a complex listric fault surface. During the iteration process of the HIIA, both the fault geometry and slip distribution of the Beichuan and Pengguan faults converge to optimal values, indicating a Beichuan fault (BCF) model with a continuous listric shape and gradual steepening from the southwest to the northeast, which is highly consistent with geological survey results. Both the synthetic and real-world case studies show that the HIIA and the CMFF are superior to the conventional fault modelling method based on rectangular planes and that these models have the potential for use in more integrated research involving inversion studies, such as joint slip/curved-fault-geometry inversions that take into account data resolving power.

Description: Globally gridded estimates of monthly-mean anomalies of terrestrial water storage (TWS) are estimated from the most recent GRACE release 05a of GFZ Potsdam in order to provide non-geodetic users a convenient access to state-of-the-art GRACE monitoring data. We use an ensemble of five global land model simulations with different physics and different atmospheric forcing to obtain reliable gridded scaling factors required to correct for spatial leakage introduced during data processing. To allow for the application of this data-set for large-scale monitoring tasks, model validation efforts, and subsequently also data assimilation experiments, globally gridded estimates of TWS uncertainties that include (i) measurement, (ii) leakage and (iii) re-scaling errors are provided as well. The results are generally consistent with the gridded data provided by Tellus, but deviate in some basins which are largely affected by the uncertainties of the model information required for re-scaling, where the approach based on the median of a small ensemble of global land models introduced in this paper leads to more robust results.

Description: Regional recovery of the disturbing gravitational potential in the area of Central Europe from satellite gravitational gradients data is discussed in this contribution. The disturbing gravitational potential is obtained by inverting surface integral formulas which transform the disturbing gravitational potential onto disturbing gravitational gradients in the spherical local north-oriented frame. Two numerical approaches that solve the inverse problem are considered. In the first approach, the integral formulas are rigorously decomposed into two parts, that is, the effects of the gradient data within near and distant zones. While the effect of the near zone data is sought as an inverse problem, the effect of the distant zone data is synthesized from the global gravitational model GGM05S using spectral weights given by truncation error coefficients up to the degree 150. In the second approach, a reference gravitational field up to the degree 180 is applied to reduce and smooth measured gravitational gradients. In both cases we recovered the disturbing gravitational potential from each of the four well-measured gravitational gradients of the GOCE satellite separately as well as from their combination. Obtained results are compared with the EGM2008, DIR-r2, TIM-r2 and SPW-r2 global gravitational models. The best fit was achieved for EGM2008 and the second approach combining all four well-measured gravitational gradients with rms of 1.231 m 2  s –2 .

Description: We present efficient Fourier-domain algorithms for modelling gravity effects due to topographic masses. The well-known Parker's formula originally based on the standard fast Fourier transform (FFT) algorithm is modified by applying the Gauss–FFT method instead. Numerical precision of the forward and inverse Fourier transforms embedded in Parker's formula and its extended forms are significantly improved by the Gauss–FFT method. The topographic model is composed of two major aspects, the geometry and the density. Versatile geometric representations, including the mass line model, the mass prism model, the polyhedron model and smoother topographic models interpolated from discrete data sets using high-order splines or pre-defined by analytical functions, in combination with density distributions that vary both laterally and vertically in rather arbitrary ways following exponential or general polynomial functions, now can be treated in a consistent framework by applying the Gauss–FFT method. The method presented has been numerically checked by space-domain analytical and hybrid analytical/numerical solutions already established in the literature. Synthetic and real model tests show that both the Gauss–FFT method and the standard FFT method run much faster than space-domain solutions, with the Gauss–FFT method being superior in numerical accuracy. When truncation errors are negligible, the Gauss–FFT method can provide forward results almost identical to space-domain analytical or semi-numerical solutions in much less time.