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Transcriptome-wide time series expression profiling is used to characterize the cellular response to environmental perturbations. The first step to analyzing transcriptional response data is often to cluster genes with similar responses. Here, we present a nonparametric model-based method, Dirichlet process Gaussian process mixture model (DPGP), which jointly models data clusters with a Dirichlet process and temporal dependencies with Gaussian processes. We demonstrate the accuracy of DPGP in comparison to state-of-the-art approaches using hundreds of simulated data sets. To further test our method, we apply DPGP to published microarray data from a microbial model organism exposed to stress and to novel RNA-seq data from a human cell line exposed to the glucocorticoid dexamethasone. We validate our clusters by examining local transcription factor binding and histone modifications. Our results demonstrate that jointly modeling cluster number and temporal dependencies can reveal shared regulatory mechanisms. DPGP software is freely available online at https://github.com/PrincetonUniversity/DP_GP_cluster.

Identifying latent structure in high-dimensional genomic data is essential for exploring biological processes. Here, we consider recovering gene co-expression networks from gene expression data, where each network encodes relationships between genes that are co-regulated by shared biological mechanisms. To do this, we develop a Bayesian statistical model for biclustering to infer subsets of co-regulated genes that covary in all of the samples or in only a subset of the samples. Our biclustering method, BicMix, allows overcomplete representations of the data, computational tractability, and joint modeling of unknown confounders and biological signals. Compared with related biclustering methods, BicMix recovers latent structure with higher precision across diverse simulation scenarios as compared to state-of-the-art biclustering methods. Further, we develop a principled method to recover context specific gene co-expression networks from the estimated sparse biclustering matrices. We apply BicMix to breast cancer gene expression data and to gene expression data from a cardiovascular study cohort, and we recover gene co-expression networks that are differential across ER+ and ER- samples and across male and female samples. We apply BicMix to the Genotype-Tissue Expression (GTEx) pilot data, and we find tissue specific gene networks. We validate these findings by using our tissue specific networks to identify trans-eQTLs specific to one of four primary tissues.

Background Transversions (Tv’s) are more likely to alter the amino acid sequence of proteins than transitions (Ts’s), and local deviations in the Ts:Tv ratio are indicative of evolutionary selection on genes. Whether the two different types of mutations have different effects in non-protein-coding sequences remains unknown. Genetic variants primarily impact gene expression by disrupting the binding of transcription factors (TFs) and other DNA-binding proteins. Because Tv’s cause larger changes in the shape of a DNA backbone, we hypothesized that Tv’s would have larger impacts on TF binding and gene expression. Results Here, we provide multiple lines of evidence demonstrating that Tv’s have larger impacts on regulatory DNA including analyses of TF binding motifs and allele-specific TF binding. In these analyses, we observed a depletion of Tv’s within TF binding motifs and TF binding sites. Using massively parallel population-scale reporter assays, we also provided empirical evidence that Tv’s have larger effects than Ts’s on the activity of human gene regulatory elements. Conclusions Tv’s are more likely to disrupt TF binding, resulting in larger changes in gene expression. Although the observed differences are small, these findings represent a novel, fundamental property of regulatory variation. Understanding the features of functional non-coding variation could be valuable for revealing the genetic underpinnings of complex traits and diseases in future studies.

Gene regulatory network inference is essential to uncover complex relationships among gene pathways and inform downstream experiments, ultimately enabling regulatory network re-engineering. Network inference from transcriptional time-series data requires accurate, interpretable, and efficient determination of causal relationships among thousands of genes. Here, we develop Bootstrap Elastic net regression from Time Series (BETS), a statistical framework based on Granger causality for the recovery of a directed gene network from transcriptional time-series data. BETS uses elastic net regression and stability selection from bootstrapped samples to infer causal relationships among genes. BETS is highly parallelized, enabling efficient analysis of large transcriptional data sets. We show competitive accuracy on a community benchmark, the DREAM4 100-gene network inference challenge, where BETS is one of the fastest among methods of similar performance and additionally infers whether causal effects are activating or inhibitory. We apply BETS to transcriptional time-series data of differentially-expressed genes from A549 cells exposed to glucocorticoids over a period of 12 hours. We identify a network of 2768 genes and 31,945 directed edges (FDR ≤ 0.2). We validate inferred causal network edges using two external data sources: Overexpression experiments on the same glucocorticoid system, and genetic variants associated with inferred edges in primary lung tissue in the Genotype-Tissue Expression (GTEx) v6 project. BETS is available as an open source software package at https://github.com/lujonathanh/BETS .

The American oyster Crassostrea virginica, an ecologically and economically important estuarine organism, can suffer high mortalities in areas in the Northeast United States due to Roseovarius Oyster Disease (ROD), caused by the gram-negative bacterial pathogen Roseovarius crassostreae. The goals of this research were to provide insights into: 1) the responses of American oysters to R. crassostreae, and 2) potential mechanisms of resistance or susceptibility to ROD. The responses of oysters to bacterial challenge were characterized by exposing oysters from ROD-resistant and susceptible families to R. crassostreae, followed by high-throughput sequencing of cDNA samples from various timepoints after disease challenge. Sequence data was assembled into a reference transcriptome and analyzed through differential gene expression and functional enrichment to uncover genes and processes potentially involved in responses to ROD in the American oyster. While susceptible oysters experienced constant levels of mortality when challenged with R. crassostreae, resistant oysters showed levels of mortality similar to non-challenged oysters. Oysters exposed to R. crassostreae showed differential expression of transcripts involved in immune recognition, signaling, protease inhibition, detoxification, and apoptosis. Transcripts involved in metabolism were enriched in susceptible oysters, suggesting that bacterial infection places a large metabolic demand on these oysters. Transcripts differentially expressed in resistant oysters in response to infection included the immune modulators IL-17 and arginase, as well as several genes involved in extracellular matrix remodeling. The identification of potential genes and processes responsible for defense against R. crassostreae in the American oyster provides insights into potential mechanisms of disease resistance.

Understanding firn densification is essential for interpreting ice core records, predicting ice sheet mass balance, elevation changes and future sea-level rise. Current models of firn densification on the Antarctic ice sheet (AIS), such as the Herron and Langway (1980) model are either simple semi-empirical models that rely on sparse climatic data and surface density observations or complex physics-based models that rely on poorly understood physics. In this work, we introduce a deep learning technique to study firn densification on the AIS. Our model, FirnLearn, evaluated on 225 cores, shows an average root-mean-square error of 31 kg m−3 and explained variance of 91%. We use the model to generate surface density and the depths to the $550\\,\\mathrm{kg\\,m}^{-3}$ and $830\\,\\mathrm{kg\\,m}^{-3}$ density horizons across the AIS to assess spatial variability. Comparisons with the Herron and Langway (1980) model at ten locations with different climate conditions demonstrate that FirnLearn more accurately predicts density profiles in the second stage of densification and complete density profiles without direct surface density observations. This work establishes deep learning as a promising tool for understanding firn processes and advancing towards a universally applicable firn model.

Antibodies are critical reagents to detect and characterize proteins. It is commonly understood that many commercial antibodies do not recognize their intended targets, but information on the scope of the problem remains largely anecdotal, and as such, feasibility of the goal of at least one potent and specific antibody targeting each protein in a proteome cannot be assessed. Focusing on antibodies for human proteins, we have scaled a standardized characterization approach using parental and knockout cell lines (Laflamme et al., 2019) to assess the performance of 614 commercial antibodies for 65 neuroscience-related proteins. Side-by-side comparisons of all antibodies against each target, obtained from multiple commercial partners, have demonstrated that: (i) more than 50% of all antibodies failed in one or more applications, (ii) yet, ~50–75% of the protein set was covered by at least one high-performing antibody, depending on application, suggesting that coverage of human proteins by commercial antibodies is significant; and (iii) recombinant antibodies performed better than monoclonal or polyclonal antibodies. The hundreds of underperforming antibodies identified in this study were found to have been used in a large number of published articles, which should raise alarm. Encouragingly, more than half of the underperforming commercial antibodies were reassessed by the manufacturers, and many had alterations to their recommended usage or were removed from the market. This first study helps demonstrate the scale of the antibody specificity problem but also suggests an efficient strategy toward achieving coverage of the human proteome; mine the existing commercial antibody repertoire, and use the data to focus new renewable antibody generation efforts.

Environmental stimuli commonly act via changes in gene regulation. Human-genome-scale assays to measure such responses are indirect or require knowledge of the transcription factors (TFs) involved. Here, we present the use of human genome-wide high-throughput reporter assays to measure environmentally-responsive regulatory element activity. We focus on responses to glucocorticoids (GCs), an important class of pharmaceuticals and a paradigmatic genomic response model. We assay GC-responsive regulatory activity across >10 8 unique DNA fragments, covering the human genome at >50×. Those assays directly detected thousands of GC-responsive regulatory elements genome-wide. We then validate those findings with measurements of transcription factor occupancy, histone modifications, chromatin accessibility, and gene expression. We also detect allele-specific environmental responses. Notably, the assays did not require knowledge of GC response mechanisms. Thus, this technology can be used to agnostically quantify genomic responses for which the underlying mechanism remains unknown. Quantification of genomic responses to environmental stimuli by current genome-scale assays is limited to indirect measurements or requires knowledge of the transcription factors involved. Here, the authors use genome-wide high-throughput reporter assays to agnostically map enhancer activity in response to glucocorticoid treatment across the human genome.

The Greenland and Antarctic ice sheets are covered in a layer of porous firn. Knowledge of firn structure improves our understanding of ice sheet mass balance, supra- and englacial hydrology, and ice core paleoclimate records. While macroscale firn properties, such as firn density, are relatively easy to measure in the field or lab, more intensive measurements of microstructural properties are necessary to reduce uncertainty in remote sensing observations of mass balance, model meltwater infiltration, and constrain ice age – gas age differences in ice cores. Additionally, as the duration and extent of surface melting increases, refreezing meltwater will greatly alter firn structure. Field observations of firn grain size and ice layer stratigraphy are required to test and validate physical models that simulate the ice-sheet-wide evolution of the firn layer. However, visually measuring grain size and ice layer distributions is tedious, is time-consuming, and can be subjective depending on the method. Here we demonstrate a method to systematically map firn core grain size and ice layer stratigraphy using a near-infrared hyperspectral imager (NIR-HSI; 900–1700 nm). We scanned 14 firn cores spanning ∼ 1000 km across western Greenland’s percolation zone with the NIR-HSI mounted on a linear translation stage in a cold laboratory. We leverage the relationship between effective grain size, a measure of NIR light absorption by firn grains, and NIR reflectance to produce high-resolution (0.4 mm) maps of effective grain size and ice layer stratigraphy. We show the NIR-HSI reproduces visually identified ice layer stratigraphy and infiltration ice content across all cores. Effective grain sizes change synchronously with traditionally measured grain radii with depth, although effective grains in each core are 1.5× larger on average, which is largely related to the differences in measurement techniques. To demonstrate the utility of the firn stratigraphic maps produced by the NIR-HSI, we track the 2012 melt event across the transect and assess its impact on deep firn structure by quantifying changes to infiltration ice content and grain size. These results indicate that NIR-HSI firn core analysis is a robust technique that can document deep and long-lasting changes to the firn column from meltwater percolation while quickly and accurately providing detailed firn stratigraphy datasets necessary for firn research applications.

Temperature sensors installed in a grid of nine full-depth boreholes drilled in the southwestern ablation zone of the Greenland Ice Sheet recorded cooling in discrete sections of ice over time within the lowest third of the ice column in most boreholes. Rates of temperature change outpace cooling expected from vertical conduction alone. Additionally, observed temperature profiles deviate significantly from the site-average thermal profile that is shaped by all thermomechanical processes upstream. These deviations imply recent, localized changes to the basal thermal state in the boreholes. Although numerous heat sources exist to add energy and warm ice as it moves from the central divide towards the margin such as strain heat from internal deformation, latent heat from refreezing meltwater, and the conduction of geothermal heat across the ice-bedrock interface, identifying heat sinks proves more difficult. After eliminating possible mechanisms that could cause cooling, we find that the observed cooling is a manifestation of previous warming in near-basal ice. Thermal decay after latent heat is released from freezing water in basal crevasses is the most likely mechanism resulting in the transient evolution of temperature and the vertical thermal structure observed at our site. We argue basal crevasses are a viable englacial heat source in the basal ice of Greenland's ablation zone and may have a controlling influence on the temperature structure of the near-basal ice.