Web-based Gene Pathogenicity Analysis (WGPA): a web platform to interpret gene pathogenicity from personal genome data

UNLABELLED: As the volume of patient-specific genome sequences increases the focus of biomedical research is switching from the detection of disease-mutations to their interpretation. To this end a number of techniques have been developed that use mutation data collected within a population to predict whether individual genes are likely to be disease-causing or not. As both sequence data and associated analysis tools proliferate, it becomes increasingly difficult for the community to make sense of these data and their implications. Moreover, no single analysis tool is likely to capture all relevant genomic features that contribute to the gene's pathogenicity. Here, we introduce Web-based Gene Pathogenicity Analysis (WGPA), a web-based tool to analyze genes impacted by mutations and rank them through the integration of existing prioritization tools, which assess different aspects of gene pathogenicity using population-level sequence data. Additionally, to explore the polygenic contribution of mutations to disease, WGPA implements gene set enrichment analysis to prioritize disease-causing genes and gene interaction networks, therefore providing a comprehensive annotation of personal genomes data in disease. AVAILABILITY AND IMPLEMENTATION: wgpa.systems-genetics.net

HST/WFC3 transmission spectroscopy of the cold rocky planet TRAPPIST-1h

TRAPPIST-1 is a nearby ultra-cool dwarf star transited by seven rocky planets. We observed three transits of its outermost planet, TRAPPIST-1h, using the G141 grism of the Wide Field Camera 3 instrument aboard the Hubble Space Telescope to place constraints on its potentially cold atmosphere. In order to deal with the effect of stellar contamination, we model TRAPPIST-1 active regions as portions of a cooler and a hotter photosphere, and generate multi-temperature models that we compare to the out-of-transit spectrum of the star. Using the inferred spot parameters, we produce corrected transmission spectra for planet h under five transit configurations and compare these data to planetary atmospheric transmission models using the forward model CHIMERA. Our analysis reveals that TRAPPIST-1h is unlikely to host an aerosol-free H/He-dominated atmosphere. While the current data precision limits the constraints we can put on the planetary atmosphere, we find that the likeliest scenario is that of a flat, featureless transmission spectrum in the WFC3/G141 bandpass due to a high mean molecular weight atmosphere (>1000x solar), no atmosphere, or an opaque aerosol layer, all in absence of stellar contamination. This work outlines the limitations of modeling active photospheric regions with theoretical stellar spectra, and those brought by our lack of knowledge of the photospheric structure of ultracool dwarf stars. Further characterization of the planetary atmosphere of TRAPPIST-1h would require higher precision measurements over wider wavelengths, which will be possible with the James Webb Space Telescope

LBT transmission spectroscopy of HAT-P-12b: confirmation of a cloudy atmosphere with no significant alkali features

The hot sub-Saturn-mass exoplanet HAT-P-12b is an ideal target for transmission spectroscopy because of its inflated radius. We observed one transit of the planet with the multi-object double spectrograph (MODS) on the Large Binocular Telescope (LBT) with the binocular mode and obtained an atmosphere transmission spectrum with a wavelength coverage of $\sim$ 0.4 -- 0.9 $\mathrm{\mu}$m. The spectrum is relatively flat and does not show any significant sodium or potassium absorption features. Our result is consistent with the revised Hubble Space Telescope (HST) transmission spectrum of a previous work, except that the HST result indicates a tentative detection of potassium. The potassium discrepancy could be the result of statistical fluctuation of the HST dataset. We fit the planetary transmission spectrum with an extensive grid of cloudy models and confirm the presence of high-altitude clouds in the planetary atmosphere. The fit was performed on the combined LBT and HST spectrum, which has an overall wavelength range of 0.4 -- 1.6 $\mathrm{\mu}$m. The LBT/MODS spectrograph has unique advantages in transmission spectroscopy observations because it can cover a wide wavelength range with a single exposure and acquire two sets of independent spectra simultaneously.Comment: 14 pages, 12 figures. Accepted for publication in Astronomy & Astrophysic

A common genetic variant of a mitochondrial RNA processing enzyme predisposes to insulin resistance

Mitochondrial energy metabolism plays an important role in the pathophysiology of insulin resistance. Recently, a missense N437S variant was identified in the MRPP3 gene, which encodes a mitochondrial RNA processing enzyme within the RNase P complex, with predicted impact on metabolism. We used CRISPR-Cas9 genome editing to introduce this variant into the mouse Mrpp3 gene and show that the variant causes insulin resistance on a high-fat diet. The variant did not influence mitochondrial gene expression markedly, but instead, it reduced mitochondrial calcium that lowered insulin release from the pancreatic islet β cells of the Mrpp3 variant mice. Reduced insulin secretion resulted in lower insulin levels that contributed to imbalanced metabolism and liver steatosis in the Mrpp3 variant mice on a high-fat diet. Our findings reveal that the MRPP3 variant may be a predisposing factor to insulin resistance and metabolic disease in the human population

Fair game: exploring the dynamics, perception and environmental impact of ‘surplus’ wild foods in England 10kya-present

This paper brings together zooarchaeological data from Neolithic to Post-medieval sites in England to explore the plasticity of cultural attitudes to the consumption of wild animals. It shows how, through time, game has been considered variously as ‘tabooed’ and ‘edible’, each having implications for patterns of biodiversity and wildlife management. The essential points being made are that deeper-time studies can reveal how human perceptions of ‘surplus foods’ have the potential to both create and remedy problems of environmental sustainability and food security. Perhaps more significantly, this paper argues that understanding the bio-cultural past of edible wild animal species has the potential to transform human attitudes to game in the present. This is important at a time when food security and the production of surplus are pressing national and global concerns

Stronger diversity effects with increased environmental stress : a study of multitrophic interactions between oak, powdery mildew and ladybirds

Recent research has suggested that increasing neighbourhood tree species diversity may mitigate the impact of pests or pathogens by supporting the activities of their natural enemies and/or reducing the density of available hosts. In this study, we attempted to assess these mechanisms in a multitrophic study system of young oak (Quercus), oak powdery mildew (PM, caused by Erysiphe spp.) and a mycophagous ladybird (Psyllobora vigintiduo-punctata). We assessed ladybird mycophagy on oak PM in function of different neighbourhood tree species compositions. We also evaluated whether these species interactions were modulated by environmental conditions as suggested by the Stress Gradient Hypothesis. We adopted a complementary approach of a field experiment where we monitored oak saplings subjected to a reduced rainfall gradient in a young planted forest consisting of different tree species mixtures, as well as a lab experiment where we independently evaluated the effect of different watering treatments on PM infections and ladybird mycophagy. In the field experiment, we found effects of neighbourhood tree species richness on ladybird mycophagy becoming more positive as the target trees received less water. This effect was only found as weather conditions grew drier. In the lab experiment, we found a preference of ladybirds to graze on infected leaves from trees that received less water. We discuss potential mechanisms that might explain this preference, such as emissions of volatile leaf chemicals. Our results are in line with the expectations of the Natural Enemies Hypothesis and support the hypothesis that biodiversity effects become stronger with increased environmental stress

Asmparts: assembly of biological model parts

We propose a new computational tool to produce models of biological systems by assembling models from biological parts. Our software not only takes advantage of modularity, but it also enforces standardisation in part characterisation by considering a model of each part. We have used model parts in SBML to design transcriptional networks. Our software is open source, it works in linux and windows platforms, and it could be used to automatically produce models in a server. Our tool not only facilitates model design, but it will also help to promote the establishment of a registry of model parts

A Bayesian Approach for Analysis of Whole-Genome Bisulphite Sequencing Data Identifies Disease-Associated Changes in DNA Methylation

DNA methylation is a key epigenetic modification involved in gene regulation whose contribution to disease susceptibility remains to be fully understood. Here, we present a novel Bayesian smoothing approach (called ABBA) to detect differentially methylated regions (DMRs) from whole-genome bisulphite sequencing (WGBS). We also show how this approach can be leveraged to identify disease-associated changes in DNA methylation, suggesting mechanisms through which these alterations might affect disease. From a data modeling perspective, ABBA has the distinctive feature of automatically adapting to different correlation structures in CpG methylation levels across the genome whilst taking into account the distance between CpG sites as a covariate. Our simulation study shows that ABBA has greater power to detect DMRs than existing methods, providing an accurate identification of DMRs in the large majority of simulated cases. To empirically demonstrate the method's efficacy in generating biological hypotheses, we performed WGBS of primary macrophages derived from an experimental rat system of glomerulonephritis and used ABBA to identify >1,000 disease-associated DMRs. Investigation of these DMRs revealed differential DNA methylation localized to a 600bp region in the promoter of the Ifitm3 gene. This was confirmed by ChIP-seq and RNA-seq analyses, showing differential transcription factor binding at the Ifitm3 promoter by JunD (an established determinant of glomerulonephritis) and a consistent change in Ifitm3 expression. Our ABBA analysis allowed us to propose a new role for Ifitm3 in the pathogenesis of glomerulonephritis via a mechanism involving promoter hypermethylation that is associated with Ifitm3 repression in the rat strain susceptible to glomerulonephritis.This research was funded by Engineering and Physical Sciences Research Council Grant EP/K030760/1 (L.B.), The Alan Turing Institute under the EPSRC grant EP/N510129/1 (L.B., P.D.), Royal Society IE110977 (L.B., P.D.), European Union (European Social Fund - ESF), Greek national funds through the Operational Program "Education and Lifelong Learning'' of the National Strategic Reference Framework (NSRF), project ARISTEIA (P.D.), Duke-NUS Medical School and Singapore Ministry of Health (O.J.L.R., E.P.), a Medical Research Council Chain-Florey fellowship (T.O.), the Medical Research Council (MR/M004716/1 to J.B. and E.P.) and by Kidney Research UK - RP9/2013 (J.B.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Extended pharmacodynamic responses observed upon PROTAC-mediated degradation of RIPK2.

Proteolysis-Targeting Chimeras (PROTACs) are heterobifunctional small-molecules that can promote the rapid and selective proteasome-mediated degradation of intracellular proteins through the recruitment of E3 ligase complexes to non-native protein substrates. The catalytic mechanism of action of PROTACs represents an exciting new modality in drug discovery that offers several potential advantages over traditional small-molecule inhibitors, including the potential to deliver pharmacodynamic (PD) efficacy which extends beyond the detectable pharmacokinetic (PK) presence of the PROTAC, driven by the synthesis rate of the protein. Herein we report the identification and development of PROTACs that selectively degrade Receptor-Interacting Serine/Threonine Protein Kinase 2 (RIPK2) and demonstrate in vivo degradation of endogenous RIPK2 in rats at low doses and extended PD that persists in the absence of detectable compound. This disconnect between PK and PD, when coupled with low nanomolar potency, offers the potential for low human doses and infrequent dosing regimens with PROTAC medicines