OmicsView: Omics data analysis through interactive visual analytics.

With advances in NGS technologies, transcriptional profiling of human tissue across many diseases is becoming more routine, leading to the generation of petabytes of data deposited in public repositories. There is a need for bench scientists with little computational expertise to be able to access and mine this data to understand disease pathology, identify robust biomarkers of disease and the effect of interventions (in vivo or in vitro). To this end we release an open source analytics and visualization platform for expression data called OmicsView, http://omicsview.org. This platform comes preloaded with 1000 s of samples across many disease areas and normal tissue, including the GTEx database, all processed with a harmonized pipeline. We demonstrate the power and ease-of-use of the platform by means of a Crohn's disease data mining exercise where we can quickly uncover disease pathology and identify strong biomarkers of disease and response to treatment.

CellDepot: A Unified Repository for scRNA-seq Data and Visual Exploration.

CellDepot containing over 270 datasets from 8 species and many tissues serves as an integrated web application to empower scientists in exploring single-cell RNA-seq (scRNA-seq) datasets and comparing the datasets among various studies through a user-friendly interface with advanced visualization and analytical capabilities. To begin with, it provides an efficient data management system that users can upload single cell datasets and query the database by multiple attributes such as species and cell types. In addition, the graphical multi-logic, multi-condition query builder and convenient filtering tool backed by MySQL database system, allows users to quickly find the datasets of interest and compare the expression of gene(s) across these. Moreover, by embedding the cellxgene VIP tool, CellDepot enables fast exploration of individual dataset in the manner of interactivity and scalability to gain more refined insights such as cell composition, gene expression profiles, and differentially expressed genes among cell types by leveraging more than 20 frequently applied plotting functions and high-level analysis methods in single cell research. In summary, the web portal available at http://celldepot.bxgenomics.com, prompts large scale single cell data sharing, facilitates meta-analysis and visualization, and encourages scientists to contribute to the single-cell community in a tractable and collaborative way. Finally, CellDepot is released as open-source software under MIT license to motivate crowd contribution, broad adoption, and local deployment for private datasets.

Systematic single-variant and gene-based association testing of thousands of phenotypes in 394,841 UK Biobank exomes.

Genome-wide association studies have successfully discovered thousands of common variants associated with human diseases and traits, but the landscape of rare variations in human disease has not been explored at scale. Exome-sequencing studies of population biobanks provide an opportunity to systematically evaluate the impact of rare coding variations across a wide range of phenotypes to discover genes and allelic series relevant to human health and disease. Here, we present results from systematic association analyses of 4,529 phenotypes using single-variant and gene tests of 394,841 individuals in the UK Biobank with exome-sequence data. We find that the discovery of genetic associations is tightly linked to frequency and is correlated with metrics of deleteriousness and natural selection. We highlight biological findings elucidated by these data and release the dataset as a public resource alongside the Genebass browser for rapidly exploring rare-variant association results.

The burden of rare protein-truncating genetic variants on human lifespan.

Genetic predisposition has been shown to contribute substantially to the age at which we die. Genome-wide association studies (GWASs) have linked more than 20 loci to phenotypes related to human lifespan1. However, little is known about how lifespan is impacted by gene loss of function. Through whole-exome sequencing of 352,338 UK Biobank participants of European ancestry, we assessed the relevance of protein-truncating variant (PTV) gene burden on individual and parental survival. We identified four exome-wide significant (P < 4.2 × 10-7) human lifespan genes, BRCA1, BRCA2, ATM and TET2. Gene and gene-set, PTV-burden, phenome-wide association studies support known roles of these genes in cancer to impact lifespan at the population level. The TET2 PTV burden was associated with a lifespan through somatic mutation events presumably due to clonal hematopoiesis. The overlap between PTV burden and common variant-based lifespan GWASs was modest, underscoring the value of exome sequencing in well-powered biobank cohorts to complement GWASs for identifying genes underlying complex traits.

Pairwise effects between lipid GWAS genes modulate lipid plasma levels and cellular uptake.

Complex traits are characterized by multiple genes and variants acting simultaneously on a phenotype. However, studying the contribution of individual pairs of genes to complex traits has been challenging since human genetics necessitates very large population sizes, while findings from model systems do not always translate to humans. Here, we combine genetics with combinatorial RNAi (coRNAi) to systematically test for pairwise additive effects (AEs) and genetic interactions (GIs) between 30 lipid genome-wide association studies (GWAS) genes. Gene-based burden tests from 240,970 exomes show that in carriers with truncating mutations in both, APOB and either PCSK9 or LPL ("human double knock-outs") plasma lipid levels change additively. Genetics and coRNAi identify overlapping AEs for 12 additional gene pairs. Overlapping GIs are observed for TOMM40/APOE with SORT1 and NCAN. Our study identifies distinct gene pairs that modulate plasma and cellular lipid levels primarily via AEs and nominates putative drug target pairs for improved lipid-lowering combination therapies.

Increasing precipitation variability on daily-to-multiyear time scales in a warmer world.

The hydrological cycle intensifies under global warming with precipitation increases. How the increased precipitation varies temporally at a given location has vital implications for regional climates and ecosystem services. On the basis of ensemble climate model projections under a high-emission scenario, here, we show that approximately two-thirds of land on Earth will face a "wetter and more variable" hydroclimate on daily to multiyear time scales. This means wider swings between wet and dry extremes. Such an amplification of precipitation variability is particularly prominent over climatologically wet regions, with percentage increases in variability more than twice those in mean precipitation. Thermodynamic effects, linked to increased moisture availability, increase precipitation variability uniformly everywhere. It is the dynamic effects (negative) linked to weakened circulation variability that make precipitation variability changes strongly region dependent. The increase in precipitation variability poses an additional challenge to the climate resilience of infrastructures and human society.

Candida auris: A Review of Recommendations for Detection and Control in Healthcare Settings.

Candida auris is an emerging multidrug-resistant fungal pathogen. Since first reported in 2009, C. auris has caused healthcare outbreaks around the world, often involving high mortality. Identification of C. auris has been a major challenge as many common conventional laboratory methods cannot accurately detect it. Early detection and implementation of infection control practices can prevent its spread. The aim of this review is to describe recommendations for the detection and control of C. auris in healthcare settings.

Correction: Loss of the BMP Antagonist, SMOC-1, Causes Ophthalmo-Acromelic (Waardenburg Anophthalmia) Syndrome in Humans and Mice.

[This corrects the article DOI: 10.1371/journal.pgen.1002114.].

Sex-specific patterns of reproductive senescence in a long-lived reintroduced raptor.

For many species, there is evidence that breeding performance changes as an individual ages. In iteroparous species, breeding performance often increases through early life and is expected to level out or even decline (senesce) later in life. An individual's sex and conditions experienced in early life may also affect breeding performance and how this changes with age. Long-term monitoring of individuals from reintroduced populations can provide unique opportunities to explore age-related trends in breeding performance that might otherwise be logistically challenging. We used a unique dataset from a reintroduced population of white-tailed eagles Haliaeetus albicilla in Scotland, which has been intensively monitored since their initial reintroduction in 1975, to study age- and sex-specific trends in two measures of breeding performance. This monitoring provided data on the breeding performance of known individuals ranging in age from 3 to 26 years. We also explored changes in breeding performance in relation to early life experience (i.e., whether they were released or fledged in the wild). Breeding performance increased with age in early life in a similar manner for both sexes. We found stronger evidence for senescence in breeding performance in males than females. However, late-life female breeding success was associated with early life experience, while male senescent trends were not apparently impacted by conditions experienced during early life. Sexual differences in senescence mean that older males are less likely to breed successfully compared to older females, and this may influence females' mate changes later in life. This difference may suggest a linked sexual difference in survival rates or the possibility of proactive partner change by females in later life in this typically monogamous biparental species.

Enzymatic removal of ribonucleotides from DNA is essential for mammalian genome integrity and development.

The presence of ribonucleotides in genomic DNA is undesirable given their increased susceptibility to hydrolysis. Ribonuclease (RNase) H enzymes that recognize and process such embedded ribonucleotides are present in all domains of life. However, in unicellular organisms such as budding yeast, they are not required for viability or even efficient cellular proliferation, while in humans, RNase H2 hypomorphic mutations cause the neuroinflammatory disorder Aicardi-Goutières syndrome. Here, we report that RNase H2 is an essential enzyme in mice, required for embryonic growth from gastrulation onward. RNase H2 null embryos accumulate large numbers of single (or di-) ribonucleotides embedded in their genomic DNA (>1,000,000 per cell), resulting in genome instability and a p53-dependent DNA-damage response. Our findings establish RNase H2 as a key mammalian genome surveillance enzyme required for ribonucleotide removal and demonstrate that ribonucleotides are the most commonly occurring endogenous nucleotide base lesion in replicating cells.

Loss of the BMP antagonist, SMOC-1, causes Ophthalmo-acromelic (Waardenburg Anophthalmia) syndrome in humans and mice.

Ophthalmo-acromelic syndrome (OAS), also known as Waardenburg Anophthalmia syndrome, is defined by the combination of eye malformations, most commonly bilateral anophthalmia, with post-axial oligosyndactyly. Homozygosity mapping and subsequent targeted mutation analysis of a locus on 14q24.2 identified homozygous mutations in SMOC1 (SPARC-related modular calcium binding 1) in eight unrelated families. Four of these mutations are nonsense, two frame-shift, and two missense. The missense mutations are both in the second Thyroglobulin Type-1 (Tg1) domain of the protein. The orthologous gene in the mouse, Smoc1, shows site- and stage-specific expression during eye, limb, craniofacial, and somite development. We also report a targeted pre-conditional gene-trap mutation of Smoc1 (Smoc1(tm1a)) that reduces mRNA to ∼10% of wild-type levels. This gene-trap results in highly penetrant hindlimb post-axial oligosyndactyly in homozygous mutant animals (Smoc1(tm1a/tm1a)). Eye malformations, most commonly coloboma, and cleft palate occur in a significant proportion of Smoc1(tm1a/tm1a) embryos and pups. Thus partial loss of Smoc-1 results in a convincing phenocopy of the human disease. SMOC-1 is one of the two mammalian paralogs of Drosophila Pentagone, an inhibitor of decapentaplegic. The orthologous gene in Xenopus laevis, Smoc-1, also functions as a Bone Morphogenic Protein (BMP) antagonist in early embryogenesis. Loss of BMP antagonism during mammalian development provides a plausible explanation for both the limb and eye phenotype in humans and mice.

Acute multiple organ failure in adult mice deleted for the developmental regulator Wt1.

There is much interest in the mechanisms that regulate adult tissue homeostasis and their relationship to processes governing foetal development. Mice deleted for the Wilms' tumour gene, Wt1, lack kidneys, gonads, and spleen and die at mid-gestation due to defective coronary vasculature. Wt1 is vital for maintaining the mesenchymal-epithelial balance in these tissues and is required for the epithelial-to-mesenchyme transition (EMT) that generates coronary vascular progenitors. Although Wt1 is only expressed in rare cell populations in adults including glomerular podocytes, 1% of bone marrow cells, and mesothelium, we hypothesised that this might be important for homeostasis of adult tissues; hence, we deleted the gene ubiquitously in young and adult mice. Within just a few days, the mice suffered glomerulosclerosis, atrophy of the exocrine pancreas and spleen, severe reduction in bone and fat, and failure of erythropoiesis. FACS and culture experiments showed that Wt1 has an intrinsic role in both haematopoietic and mesenchymal stem cell lineages and suggest that defects within these contribute to the phenotypes we observe. We propose that glomerulosclerosis arises in part through down regulation of nephrin, a known Wt1 target gene. Protein profiling in mutant serum showed that there was no systemic inflammatory or nutritional response in the mutant mice. However, there was a dramatic reduction in circulating IGF-1 levels, which is likely to contribute to the bone and fat phenotypes. The reduction of IGF-1 did not result from a decrease in circulating GH, and there is no apparent pathology of the pituitary and adrenal glands. These findings 1) suggest that Wt1 is a major regulator of the homeostasis of some adult tissues, through both local and systemic actions; 2) highlight the differences between foetal and adult tissue regulation; 3) point to the importance of adult mesenchyme in tissue turnover.

Consanguinity mapping of congenital heart disease in a South Indian population.

BACKGROUND: Parental consanguinity is a risk factor for congenital heart disease (CHD) worldwide, suggesting that a recessive inheritance model may contribute substantially to CHD. In Bangalore, India, uncle-niece and first cousin marriages are common, presenting the opportunity for an international study involving consanguinity mapping of structural CHD. We sought to explore the recessive model of CHD by conducting a genome-wide linkage analysis utilizing high-density oligonucleotide microarrays and enrolling 83 CHD probands born to unaffected consanguineous parents. METHODOLOGY/PRINCIPAL FINDINGS: In this linkage scan involving single nucleotide polymorphism (SNP) markers, the threshold for genome-wide statistical significance was set at the standard log-of-odds (LOD) score threshold of 3.3, corresponding to 1995ratio1 odds in favor of linkage. We identified a maximal single-point LOD score of 3.76 (5754ratio1 odds) implicating linkage of CHD with the major allele (G) of rs1055061 on chromosome 14 in the HOMEZ gene, a ubiquitously expressed transcription factor containing leucine zipper as well as zinc finger motifs. Re-sequencing of HOMEZ exons did not reveal causative mutations in Indian probands. In addition, genotyping of the linked allele (G) in 325 U.S. CHD cases revealed neither genotypic nor allele frequency differences in varied CHD cases compared to 605 non-CHD controls. CONCLUSIONS/SIGNIFICANCE: Despite the statistical power of the consanguinity mapping approach, no single gene of major effect could be convincingly identified in a clinically heterogeneous sample of Indian CHD cases born to consanguineous parents. However, we are unable to exclude the possibility that noncoding regions of HOMEZ may harbor recessive mutations leading to CHD in the Indian population. Further research involving large multinational cohorts of patients with specific subtypes of CHD is needed to attempt replication of the observed linkage peak on chromosome 14. In addition, we anticipate that a targeted re-sequencing approach may complement linkage analysis in future studies of recessive mutation detection in CHD.

Finding unique filter sets in PLATO: a precursor to efficient interaction analysis in GWAS data.

The methods to detect gene-gene interactions between variants in genome-wide association study (GWAS) datasets have not been well developed thus far. PLATO, the Platform for the Analysis, Translation and Organization of large-scale data, is a filter-based method bringing together many analytical methods simultaneously in an effort to solve this problem. PLATO filters a large, genomic dataset down to a subset of genetic variants, which may be useful for interaction analysis. As a precursor to the use of PLATO for the detection of gene-gene interactions, the implementation of a variety of single locus filters was completed and evaluated as a proof of concept. To streamline PLATO for efficient epistasis analysis, we determined which of 24 analytical filters produced redundant results. Using a kappa score to identify agreement between filters, we grouped the analytical filters into 4 filter classes; thus all further analyses employed four filters. We then tested the MAX statistic put forth by Sladek et al. (1) in simulated data exploring a number of genetic models of modest effect size. To find the MAX statistic, the four filters were run on each SNP in each dataset and the smallest p-value among the four results was taken as the final result. Permutation testing was performed to empirically determine the p-value. The power of the MAX statistic to detect each of the simulated effects was determined in addition to the Type 1 error and false positive rates. The results of this simulation study demonstrates that PLATO using the four filters incorporating the MAX statistic has higher power on average to find multiple types of effects and a lower false positive rate than any of the individual filters alone. In the future we will extend PLATO with the MAX statistic to interaction analyses for large-scale genomic datasets.

Replication analysis identifies TYK2 as a multiple sclerosis susceptibility factor.

In a recent genome-wide association study (GWAS) based on 12,374 non-synonymous single nucleotide polymorphisms we identified a number of candidate multiple sclerosis susceptibility genes. Here, we describe the extended analysis of 17 of these loci undertaken using an additional 4234 patients, 2983 controls and 2053 trio families. In the final analysis combining all available data, we found that evidence for association was substantially increased for one of the 17 loci, rs34536443 from the tyrosine kinase 2 (TYK2) gene (P=2.7 x 10(-6), odds ratio=1.32 (1.17-1.47)). This single nucleotide polymorphism results in an amino acid substitution (proline to alanine) in the kinase domain of TYK2, which is predicted to influence the levels of phosphorylation and therefore activity of the protein and so is likely to have a functional role in multiple sclerosis.

Projected increase in continental runoff due to plant responses to increasing carbon dioxide.

In addition to influencing climatic conditions directly through radiative forcing, increasing carbon dioxide concentration influences the climate system through its effects on plant physiology. Plant stomata generally open less widely under increased carbon dioxide concentration, which reduces transpiration and thus leaves more water at the land surface. This driver of change in the climate system, which we term 'physiological forcing', has been detected in observational records of increasing average continental runoff over the twentieth century. Here we use an ensemble of experiments with a global climate model that includes a vegetation component to assess the contribution of physiological forcing to future changes in continental runoff, in the context of uncertainties in future precipitation. We find that the physiological effect of doubled carbon dioxide concentrations on plant transpiration increases simulated global mean runoff by 6 per cent relative to pre-industrial levels; an increase that is comparable to that simulated in response to radiatively forced climate change (11 +/- 6 per cent). Assessments of the effect of increasing carbon dioxide concentrations on the hydrological cycle that only consider radiative forcing will therefore tend to underestimate future increases in runoff and overestimate decreases. This suggests that freshwater resources may be less limited than previously assumed under scenarios of future global warming, although there is still an increased risk of drought. Moreover, our results highlight that the practice of assessing the climate-forcing potential of all greenhouse gases in terms of their radiative forcing potential relative to carbon dioxide does not accurately reflect the relative effects of different greenhouse gases on freshwater resources.

Inference in ensemble experiments.

We consider inference based on ensembles of climate model evaluations, and contrast the Monte Carlo approach, in which the evaluations are selected at random from the model-input space, with a more overtly statistical approach using emulators and experimental design.