Genome-wide association and HLA fine-mapping studies identify risk loci and genetic pathways underlying allergic rhinitis

Allergic rhinitis is the most common clinical presentation of allergy, affecting 400 million people worldwide, with increasing incidence in westernized countries1,2. To elucidate the genetic architecture and understand the underlying disease mechanisms, we carried out a meta-analysis of allergic rhinitis in 59,762 cases and 152,358 controls of European ancestry and identified a total of 41 risk loci for allergic rhinitis, including 20 loci not previously associated with allergic rhinitis, which were confirmed in a replication phase of 60,720 cases and 618,527 controls. Functional annotation implicated genes involved in various immune pathways, and fine mapping of the HLA region suggested amino acid variants important for antigen binding. We further performed genome-wide association study (GWAS) analyses of allergic sensitization against inhalant allergens and nonallergic rhinitis, which suggested shared genetic mechanisms across rhinitis-related traits. Future studies of the identified loci and genes might identify novel targets for treatment and prevention of allergic rhinitis

Fusion and Fission of Genes Define a Metric between Fungal Genomes

Gene fusion and fission events are key mechanisms in the evolution of gene architecture, whose effects are visible in protein architecture when they occur in coding sequences. Until now, the detection of fusion and fission events has been performed at the level of protein sequences with a post facto removal of supernumerary links due to paralogy, and often did not include looking for events defined only in single genomes. We propose a method for the detection of these events, defined on groups of paralogs to compensate for the gene redundancy of eukaryotic genomes, and apply it to the proteomes of 12 fungal species. We collected an inventory of 1,680 elementary fusion and fission events. In half the cases, both composite and element genes are found in the same species. Per-species counts of events correlate with the species genome size, suggesting a random mechanism of occurrence. Some biological functions of the genes involved in fusion and fission events are slightly over- or under-represented. As already noted in previous studies, the genes involved in an event tend to belong to the same functional category. We inferred the position of each event in the evolution tree of the 12 fungal species. The event localization counts for all the segments of the tree provide a metric that depicts the “recombinational” phylogeny among fungi. A possible interpretation of this metric as distance in adaptation space is proposed

Virtual pathway explorer (viPEr) and pathway enrichment analysis tool (PEANuT): creating and analyzing focus networks to identify cross-talk between molecules and pathways

BACKGROUND: Interpreting large-scale studies from microarrays or next-generation sequencing for further experimental testing remains one of the major challenges in quantitative biology. Combining expression with physical or genetic interaction data has already been successfully applied to enhance knowledge from all types of high-throughput studies. Yet, toolboxes for navigating and understanding even small gene or protein networks are poorly developed. RESULTS: We introduce two Cytoscape plug-ins, which support the generation and interpretation of experiment-based interaction networks. The virtual pathway explorer viPEr creates so-called focus networks by joining a list of experimentally determined genes with the interactome of a specific organism. viPEr calculates all paths between two or more user-selected nodes, or explores the neighborhood of a single selected node. Numerical values from expression studies assigned to the nodes serve to score identified paths. The pathway enrichment analysis tool PEANuT annotates networks with pathway information from various sources and calculates enriched pathways between a focus and a background network. Using time series expression data of atorvastatin treated primary hepatocytes from six patients, we demonstrate the handling and applicability of viPEr and PEANuT. Based on our investigations using viPEr and PEANuT, we suggest a role of the FoxA1/A2/A3 transcriptional network in the cellular response to atorvastatin treatment. Moreover, we find an enrichment of metabolic and cancer pathways in the Fox transcriptional network and demonstrate a patient-specific reaction to the drug. CONCLUSIONS: The Cytoscape plug-in viPEr integrates –omics data with interactome data. It supports the interpretation and navigation of large-scale datasets by creating focus networks, facilitating mechanistic predictions from –omics studies. PEANuT provides an up-front method to identify underlying biological principles by calculating enriched pathways in focus networks. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12864-015-2017-z) contains supplementary material, which is available to authorized users

Voltage- and light-controlled spin properties of a two-dimensional hole gas in p-type GaAs/AlAs resonant tunneling diodes

We have investigated the spin properties of a two-dimensional hole gas (2DHG) formed at the contact layer of a p-type GaAs/AlAs resonant tunneling diode (RTD). We have measured the polarized-resolved photoluminescence of the RTD as a function of bias voltage, laser intensity and external magnetic field up to 15T. By tuning the voltage and the laser intensity, we are able to change the spin-splitting from the 2DHG from almost 0 meV to 5 meV and its polarization degree from − 40% to + 50% at 15T. These results are attributed to changes of the local electric field applied to the two-dimensional gas which affects the valence band and the hole Rashba spin–orbit effect

Precision medicine driven by cancer systems biology

Molecular insights from genome and systems biology are influencing how cancer is diagnosed and treated. We critically evaluate big data challenges in precision medicine. The melanoma research community has identified distinct subtypes involving chronic sun-induced damage and the mitogen-activated protein kinase driver pathway. In addition, despite low mutation burden, non-genomic mitogen-activated protein kinase melanoma drivers are found in membrane receptors, metabolism, or epigenetic signaling with the ability to bypass central mitogen-activated protein kinase molecules and activating a similar program of mitogenic effectors. Mutation hotspots, structural modeling, UV signature, and genomic as well as non-genomic mechanisms of disease initiation and progression are taken into consideration to identify resistance mutations and novel drug targets. A comprehensive precision medicine profile of a malignant melanoma patient illustrates future rational drug targeting strategies. Network analysis emphasizes an important role of epigenetic and metabolic master regulators in oncogenesis. Co-occurrence of driver mutations in signaling, metabolic, and epigenetic factors highlights how cumulative alterations of our genomes and epigenomes progressively lead to uncontrolled cell proliferation. Precision insights have the ability to identify independent molecular pathways suitable for drug targeting. Synergistic treatment combinations of orthogonal modalities including immunotherapy, mitogen-activated protein kinase inhibitors, epigenetic inhibitors, and metabolic inhibitors have the potential to overcome immune evasion, side effects, and drug resistance

Protein complexes are under evolutionary selection to assemble via ordered pathways

Is the order in which proteins assemble into complexes important for biological function? Here, we seek to address this by searching for evidence of evolutionary selection for ordered protein complex assembly. First, we experimentally characterize the assembly pathways of several heteromeric complexes and show that they can be simply predicted from their three-dimensional structures. Then, by mapping gene fusion events identified from fully sequenced genomes onto protein complex assembly pathways, we demonstrate evolutionary selection for conservation of assembly order. Furthermore, using structural and high-throughput interaction data, we show that fusion tends to optimize assembly by simplifying protein complex topologies. Finally, we observe protein structural constraints on the gene order of fusion that impact the potential for fusion to affect assembly. Together, these results reveal the intimate relationships among protein assembly, quaternary structure, and evolution and demonstrate on a genome-wide scale the biological importance of ordered assembly pathways

Integrated genomic characterization of pancreatic ductal adenocarcinoma

We performed integrated genomic, transcriptomic, and proteomic profiling of 150 pancreatic ductal adenocarcinoma (PDAC) specimens, including samples with characteristic low neoplastic cellularity. Deep whole-exome sequencing revealed recurrent somatic mutations in KRAS, TP53, CDKN2A, SMAD4, RNF43, ARID1A, TGFβR2, GNAS, RREB1, and PBRM1. KRAS wild-type tumors harbored alterations in other oncogenic drivers, including GNAS, BRAF, CTNNB1, and additional RAS pathway genes. A subset of tumors harbored multiple KRAS mutations, with some showing evidence of biallelic mutations. Protein profiling identified a favorable prognosis subset with low epithelial-mesenchymal transition and high MTOR pathway scores. Associations of non-coding RNAs with tumor-specific mRNA subtypes were also identified. Our integrated multi-platform analysis reveals a complex molecular landscape of PDAC and provides a roadmap for precision medicine