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1. Integration of anatomy ontology data with protein–protein interaction networks improves the candidate gene prediction accuracy for anatomical entities

   https://doi.org/10.1186/s12859-020-03773-2  

   Fernando, Pasan C. ; Mabee, Paula M. ; Zeng, Erliang ( December 2020 , BMC Bioinformatics)

   Abstract Background Identification of genes responsible for anatomical entities is a major requirement in many fields including developmental biology, medicine, and agriculture. Current wet lab techniques used for this purpose, such as gene knockout, are high in resource and time consumption. Protein–protein interaction (PPI) networks are frequently used to predict disease genes for humans and gene candidates for molecular functions, but they are rarely used to predict genes for anatomical entities. Moreover, PPI networks suffer from network quality issues, which can be a limitation for their usage in predicting candidate genes. Therefore, we developed an integrative framework to improve the candidate gene prediction accuracy for anatomical entities by combining existing experimental knowledge about gene-anatomical entity relationships with PPI networks using anatomy ontology annotations. We hypothesized that this integration improves the quality of the PPI networks by reducing the number of false positive and false negative interactions and is better optimized to predict candidate genes for anatomical entities. We used existing Uberon anatomical entity annotations for zebrafish and mouse genes to construct gene networks by calculating semantic similarity between the genes. These anatomy-based gene networks were semantic networks, as they were constructed based on the anatomy ontology annotations that were obtained from the experimental data in the literature. We integrated these anatomy-based gene networks with mouse and zebrafish PPI networks retrieved from the STRING database and compared the performance of their network-based candidate gene predictions. Results According to evaluations of candidate gene prediction performance tested under four different semantic similarity calculation methods (Lin, Resnik, Schlicker, and Wang), the integrated networks, which were semantically improved PPI networks, showed better performances by having higher area under the curve values for receiver operating characteristic and precision-recall curves than PPI networks for both zebrafish and mouse. Conclusion Integration of existing experimental knowledge about gene-anatomical entity relationships with PPI networks via anatomy ontology improved the candidate gene prediction accuracy and optimized them for predicting candidate genes for anatomical entities. 

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2. PANGEA: a new gene set enrichment tool for Drosophila and common research organisms

   https://doi.org/10.1093/nar/gkad331  

   Hu, Yanhui ; Comjean, Aram ; Attrill, Helen ; Antonazzo, Giulia ; Thurmond, Jim ; Chen, Weihang ; Li, Fangge ; Chao, Tiffany ; Mohr, Stephanie E ; Brown, Nicholas H ; et al ( May 2023 , Nucleic Acids Research)

   Gene set enrichment analysis (GSEA) plays an important role in large-scale data analysis, helping scientists discover the underlying biological patterns over-represented in a gene list resulting from, for example, an ‘omics’ study. Gene Ontology (GO) annotation is the most frequently used classification mechanism for gene set definition. Here we present a new GSEA tool, PANGEA (PAthway, Network and Gene-set Enrichment Analysis; https://www.flyrnai.org/tools/pangea/), developed to allow a more flexible and configurable approach to data analysis using a variety of classification sets. PANGEA allows GO analysis to be performed on different sets of GO annotations, for example excluding high-throughput studies. Beyond GO, gene sets for pathway annotation and protein complex data from various resources as well as expression and disease annotation from the Alliance of Genome Resources (Alliance). In addition, visualizations of results are enhanced by providing an option to view network of gene set to gene relationships. The tool also allows comparison of multiple input gene lists and accompanying visualisation tools for quick and easy comparison. This new tool will facilitate GSEA for Drosophila and other major model organisms based on high-quality annotated information available for these species.

    

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3. Twitter-Based Knowledge Graph for Researchers

   Vincent, Kyle ; Meno, Emma ( May 2020 , Virginia tech)

   null (Ed.)

   The Twitter-Based Knowledge Graph for Researchers project is an effort to construct a knowledge graph of computation-based tasks and corresponding outputs. It will be utilized by subject matter experts, statisticians, and developers. A knowledge graph is a directed graph of knowledge accumulated from a variety of sources. For our application, Subject Matter Experts (SMEs) are experts in their respective non-computer science fields, but are not necessarily experienced with running heavy computation on datasets. As a result, they find it difficult to generate workflows for their projects involving Twitter data and advanced analysis. Workflow management systems and libraries that facilitate computation are only practical when the users of these systems understand what analysis they need to perform. Our goal is to bridge this gap in understanding. Our queryable knowledge graph will generate a visual workflow for these experts and researchers to achieve their project goals. After meeting with our client, we established two primary deliverables. First, we needed to create an ontology of all Twitter-related information that an SME might want to answer. Secondly, we needed to build a knowledge graph based on this ontology and produce a set of APIs to trigger a set of network algorithms based on the information queried to the graph. An ontology is simply the class structure/schema for the graph. Throughout future meetings, we established some more specific additional requirements. Most importantly, the client stressed that users should be able to bring their own data and add it to our knowledge graph. As more research is completed and new technologies are released, it will be important to be able to edit and add to the knowledge graph. Next, we must be able to provide metrics about the data itself. These metrics will be useful for both our own work, and future research surrounding graph search problems and search optimization. Additionally, our system should provide users with information regarding the original domain that the algorithms and workflows were run against. That way they can choose the best workflow for their data. The project team first conducted a literature review, reading reports from the CS5604 Information Retrieval courses in 2016 and 2017 to extract information related to Twitter data and algorithms. This information was used to construct our raw ontology in Google Sheets, which contained a set of dataset-algorithm-dataset tuples. The raw ontology was then converted into nodes and edges csv files for building the knowledge graph. After implementing our original solution on a CentOS virtual machine hosted by the Virginia Tech Department of Computer Science, we transitioned our solution to Grakn, an open-source knowledge graph database that supports hypergraph functionality. When finalizing our workflow paths, we noted some nodes depended on completion of two or more inputs, representing an ”AND” edge. This phenomenon is modeled as a hyperedge with Grakn, initiating our transition from Neo4J to Grakn. Currently, our system supports queries through the console, where a user can type a Graql statement to retrieve information about data in the graph, from relationships to entities to derived rules. The user can also interact with the data via Grakn's data visualizer: Workbase. The user can enter Graql queries to visualize connections within the knowledge graph. 

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4. The Arabidopsis gene co‐expression network

   https://doi.org/10.1002/pld3.396  

   Burks, David J. ; Sengupta, Soham ; De, Ronika ; Mittler, Ron ; Azad, Rajeev K. ( April 2022 , Plant Direct)

   Identifying genes that interact to confer a biological function to an organism is one of the main goals of functional genomics. High‐throughput technologies for assessment and quantification of genome‐wide gene expression patterns have enabled systems‐level analyses to infer pathways or networks of genes involved in different functions under many different conditions. Here, we leveraged the publicly available, information‐rich RNA‐Seq datasets of the model plantArabidopsis thalianato construct a gene co‐expression network, which was partitioned into clusters or modules that harbor genes correlated by expression. Gene ontology and pathway enrichment analyses were performed to assess functional terms and pathways that were enriched within the different gene modules. By interrogating the co‐expression network for genes in different modules that associate with a gene of interest, diverse functional roles of the gene can be deciphered. By mapping genes differentially expressing under a certain condition inArabidopsisonto the co‐expression network, we demonstrate the ability of the network to uncover novel genes that are likely transcriptionally active but prone to be missed by standard statistical approaches due to their falling outside of the confidence zone of detection. To our knowledge, this is the firstA. thalianaco‐expression network constructed using the entire mRNA‐Seq datasets (>20,000) available at the NCBI SRA database. The developed network can serve as a useful resource for theArabidopsisresearch community to interrogate specific genes of interest within the network, retrieve the respective interactomes, decipher gene modules that are transcriptionally altered under certain condition or stage, and gain understanding of gene functions.

    

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5. BIN1 is a key regulator of proinflammatory and neurodegeneration-related activation in microglia

   https://doi.org/10.1186/s13024-022-00535-x  

   Sudwarts, Ari ; Ramesha, Supriya ; Gao, Tianwen ; Ponnusamy, Moorthi ; Wang, Shuai ; Hansen, Mitchell ; Kozlova, Alena ; Bitarafan, Sara ; Kumar, Prateek ; Beaulieu-Abdelahad, David ; et al ( May 2022 , Molecular Neurodegeneration)

   TheBIN1locus contains the second-most significant genetic risk factor for late-onset Alzheimer’s disease.BIN1undergoes alternate splicing to generate tissue- and cell-type-specific BIN1 isoforms, which regulate membrane dynamics in a range of crucial cellular processes. Whilst the expression of BIN1 in the brain has been characterized in neurons and oligodendrocytes in detail, information regarding microglial BIN1 expression is mainly limited to large-scale transcriptomic and proteomic data. Notably, BIN1 protein expression and its functional roles in microglia, a cell type most relevant to Alzheimer’s disease, have not been examined in depth.

   Microglial BIN1 expression was analyzed by immunostaining mouse and human brain, as well as by immunoblot and RT-PCR assays of isolated microglia or human iPSC-derived microglial cells.Bin1expression was ablated by siRNA knockdown in primary microglial cultures in vitro and Cre-lox mediated conditional deletion in adult mouse brain microglia in vivo. Regulation of neuroinflammatory microglial signatures by BIN1 in vitro and in vivo was characterized using NanoString gene panels and flow cytometry methods. The transcriptome data was explored by in silico pathway analysis and validated by complementary molecular approaches.

   Here, we characterized microglial BIN1 expression in vitro and in vivo and ascertained microglia expressed BIN1 isoforms. By silencingBin1expression in primary microglial cultures, we demonstrate that BIN1 regulates the activation of proinflammatory and disease-associated responses in microglia as measured by gene expression and cytokine production. Our transcriptomic profiling revealed key homeostatic and lipopolysaccharide (LPS)-induced inflammatory response pathways, as well as transcription factors PU.1 and IRF1 that are regulated by BIN1. Microglia-specificBin1conditional knockout in vivo revealed novel roles of BIN1 in regulating the expression of disease-associated genes while counteracting CX3CR1 signaling. The consensus from in vitro and in vivo findings showed that loss ofBin1impaired the ability of microglia to mount type 1 interferon responses to proinflammatory challenge, particularly the upregulation of a critical type 1 immune response gene,Ifitm3.

   Our convergent findings provide novel insights into microglial BIN1 function and demonstrate an essential role of microglial BIN1 in regulating brain inflammatory response and microglial phenotypic changes. Moreover, for the first time, our study shows a regulatory relationship betweenBin1andIfitm3, two Alzheimer’s disease-related genes in microglia. The requirement for BIN1 to regulateIfitm3upregulation during inflammation has important implications for inflammatory responses during the pathogenesis and progression of many neurodegenerative diseases.

    

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