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

Global analysis of the TRAPPIST Ultra-Cool Dwarf Transit Survey

ABSTRACT We conducted a global analysis of the TRAPPIST Ultra-Cool Dwarf Transit Survey – a prototype of the SPECULOOS transit search conducted with the TRAPPIST-South robotic telescope in Chile from 2011 to 2017 – to estimate the occurrence rate of close-in planets such as TRAPPIST-1b orbiting ultra-cool dwarfs. For this purpose, the photometric data of 40 nearby ultra-cool dwarfs were reanalysed in a self-consistent and fully automated manner starting from the raw images. The pipeline developed specifically for this task generates differential light curves, removes non-planetary photometric features and stellar variability, and searches for transits. It identifies the transits of TRAPPIST-1b and TRAPPIST-1c without any human intervention. To test the pipeline and the potential output of similar surveys, we injected planetary transits into the light curves on a star-by-star basis and tested whether the pipeline is able to detect them. The achieved photometric precision enables us to identify Earth-sized planets orbiting ultra-cool dwarfs as validated by the injection tests. Our planet-injection simulation further suggests a lower limit of 10 per cent on the occurrence rate of planets similar to TRAPPIST-1b with a radius between 1 and 1.3 R⊕ and the orbital period between 1.4 and 1.8 d.</jats:p

The effects of stand characteristics on the understory vegetation in Quercus petraea and Q. cerris dominated forests

The shelterwood system used in Hungary has many effects on the composition and structure of the herb layer. The aim of our study was to identify the main variables that affect the occurence of herbs and seedlings in Turkey oak-sessile oak (Quercus cerris and Q. petraea) stands. The study was carried out in the Bükk mountains, Hungary. 122 sampling plots were established in 50-150 year old oak forests, where we studied the species composition and structure of the understorey and overstorey. The occurence of herbs was affected by canopy closure, the heterogenity and patchiness of the stand, the slope and the east-west component of the aspect. The composition of saplings was significantly explained by the ratio of the two major oak species in the stand and the proximity of the adult plants. An important result for forest management was that sessile oaks were able to regenerate almost only where they were dominant in the overstorey

The Human Mitochondrial Transcriptome

SummaryThe human mitochondrial genome comprises a distinct genetic system transcribed as precursor polycistronic transcripts that are subsequently cleaved to generate individual mRNAs, tRNAs, and rRNAs. Here, we provide a comprehensive analysis of the human mitochondrial transcriptome across multiple cell lines and tissues. Using directional deep sequencing and parallel analysis of RNA ends, we demonstrate wide variation in mitochondrial transcript abundance and precisely resolve transcript processing and maturation events. We identify previously undescribed transcripts, including small RNAs, and observe the enrichment of several nuclear RNAs in mitochondria. Using high-throughput in vivo DNaseI footprinting, we establish the global profile of DNA-binding protein occupancy across the mitochondrial genome at single-nucleotide resolution, revealing regulatory features at mitochondrial transcription initiation sites and functional insights into disease-associated variants. This integrated analysis of the mitochondrial transcriptome reveals unexpected complexity in the regulation, expression, and processing of mitochondrial RNA and provides a resource for future studies of mitochondrial function (accessed at http://mitochondria.matticklab.com)

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

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

Development of the SPECULOOS exoplanet search project

SPECULOOS (Search for habitable Planets EClipsing ULtra-cOOl Stars) aims to perform a transit search on the nearest ($<40$pc) ultracool ($<3000$K) dwarf stars. The project's main motivation is to discover potentially habitable planets well-suited for detailed atmospheric characterisation with upcoming giant telescopes, like the James Webb Space Telescope (JWST) and European Large Telescope (ELT). The project is based on a network of 1m robotic telescopes, namely the four ones of the SPECULOOS-Southern Observatory (SSO) in Cerro Paranal, Chile, one telescope of the SPECULOOS-Northern Observatory (SNO) in Tenerife, and the SAINT-Ex telescope in San Pedro M\'artir, Mexico. The prototype survey of the SPECULOOS project on the 60~cm TRAPPIST telescope (Chile) discovered the TRAPPIST-1 system, composed of seven temperate Earth-sized planets orbiting a nearby (12~pc) Jupiter-sized star. In this paper, we review the current status of SPECULOOS, its first results, the plans for its development, and its connection to the Transiting Exoplanet Survey Satellite (TESS) and JWST