The Gene Ontology (GO) provides a framework and set of concepts for describing the functions of gene products from all organisms. It is specifically designed for supporting the computational ...representation of biological systems. A GO annotation is an association between a specific gene product and a GO concept, together making a statement pertinent to the function of that gene. However, the meaning of the term "function" is not as straightforward as it might seem, and has been discussed at length in both philosophical and biological circles. Here, I first review these discussions. I then present an explicit formulation of the biological model that underlies the GO and annotations, and discuss how this model relates to the broader debates on the meaning of biological function.
Abstract
PANTHER (Protein Analysis Through Evolutionary Relationships, http://pantherdb.org) is a resource for the evolutionary and functional classification of genes from organisms across the tree ...of life. We report the improvements we have made to the resource during the past two years. For evolutionary classifications, we have added more prokaryotic and plant genomes to the phylogenetic gene trees, expanding the representation of gene evolution in these lineages. We have refined many protein family boundaries, and have aligned PANTHER with the MEROPS resource for protease and protease inhibitor families. For functional classifications, we have developed an entirely new PANTHER GO-slim, containing over four times as many Gene Ontology terms as our previous GO-slim, as well as curated associations of genes to these terms. Lastly, we have made substantial improvements to the enrichment analysis tools available on the PANTHER website: users can now analyze over 900 different genomes, using updated statistical tests with false discovery rate corrections for multiple testing. The overrepresentation test is also available as a web service, for easy addition to third-party sites.
Influenza virus affects the respiratory tract by direct viral infection or by damage from the immune system response. In humans, the respiratory epithelium is the only site where the hemagglutinin ...(HA) molecule is effectively cleaved, generating infectious virus particles. Virus transmission occurs through a susceptible individual's contact with aerosols or respiratory fomites from an infected individual. The inability of the lung to perform its primary function of gas exchange can result from multiple mechanisms, including obstruction of the airways, loss of alveolar structure, loss of lung epithelial integrity from direct epithelial cell killing, and degradation of the critical extracellular matrix.Approximately 30-40% of hospitalized patients with laboratory-confirmed influenza are diagnosed with acute pneumonia. These patients who develop pneumonia are more likely to be < 5 years old, > 65 years old, Caucasian, and nursing home residents; have chronic lung or heart disease and history of smoking, and are immunocompromised.Influenza can primarily cause severe pneumonia, but it can also present in conjunction with or be followed by a secondary bacterial infection, most commonly by Staphylococcus aureus and Streptococcus pneumoniae. Influenza is associated with a high predisposition to bacterial sepsis and ARDS. Viral infections presenting concurrently with bacterial pneumonia are now known to occur with a frequency of 30-50% in both adult and pediatric populations. The H3N2 subtype has been associated with unprecedented high levels of intensive care unit (ICU) admission.Influenza A is the predominant viral etiology of acute respiratory distress syndrome (ARDS) in adults. Risk factors independently associated with ARDS are age between 36 and 55 years old, pregnancy, and obesity, while protective factors are female sex, influenza vaccination, and infections with Influenza A (H3N2) or Influenza B viruses.In the ICU, particularly during the winter season, influenza should be suspected not only in patients with typical symptoms and epidemiology, but also in patients with severe pneumonia, ARDS, sepsis with or without bacterial co-infection, as well as in patients with encephalitis, myocarditis, and rhabdomyolysis.
PANTHER-PSEP is a new software tool for predicting non-synonymous genetic variants that may play a causal role in human disease. Several previous variant pathogenicity prediction methods have been ...proposed that quantify evolutionary conservation among homologous proteins from different organisms. PANTHER-PSEP employs a related but distinct metric based on 'evolutionary preservation': homologous proteins are used to reconstruct the likely sequences of ancestral proteins at nodes in a phylogenetic tree, and the history of each amino acid can be traced back in time from its current state to estimate how long that state has been preserved in its ancestors. Here, we describe the PSEP tool, and assess its performance on standard benchmarks for distinguishing disease-associated from neutral variation in humans. On these benchmarks, PSEP outperforms not only previous tools that utilize evolutionary conservation, but also several highly used tools that include multiple other sources of information as well. For predicting pathogenic human variants, the trace back of course starts with a human 'reference' protein sequence, but the PSEP tool can also be applied to predicting deleterious or pathogenic variants in reference proteins from any of the ∼100 other species in the PANTHER database.
PANTHER-PSEP is freely available on the web at http://pantherdb.org/tools/csnpScoreForm.jsp Users can also download the command-line based tool at ftp://ftp.pantherdb.org/cSNP_analysis/PSEP/ CONTACT: pdthomas@usc.edu
Supplementary data are available at Bioinformatics online.
Adaptive immune recognition is mediated by antigen receptors on B and T cells generated by somatic recombination during lineage development. The high level of diversity resulting from this process ...posed technical limitations that previously limited the comprehensive analysis of adaptive immune recognition. Advances over the last ten years have produced data and approaches allowing insights into how T cells develop, evolutionary signatures of recombination and selection, and the features of T cell receptors that mediate epitope-specific binding and T cell activation. The size and complexity of these data have necessitated the generation of novel computational and analytical approaches, which are transforming how T cell immunology is conducted. Here we review the development and application of novel biological, theoretical, and computational methods for understanding T cell recognition and discuss the potential for improved models of receptor:antigen interactions.
The data and tools in PANTHER-a comprehensive, curated database of protein families, trees, subfamilies and functions available at http://pantherdb.org-have undergone continual, extensive improvement ...for over a decade. Here, we describe the current PANTHER process as a whole, as well as the website tools for analysis of user-uploaded data. The main goals of PANTHER remain essentially unchanged: the accurate inference (and practical application) of gene and protein function over large sequence databases, using phylogenetic trees to extrapolate from the relatively sparse experimental information from a few model organisms. Yet the focus of PANTHER has continually shifted toward more accurate and detailed representations of evolutionary events in gene family histories. The trees are now designed to represent gene family evolution, including inference of evolutionary events, such as speciation and gene duplication. Subfamilies are still curated and used to define HMMs, but gene ontology functional annotations can now be made at any node in the tree, and are designed to represent gain and loss of function by ancestral genes during evolution. Finally, PANTHER now includes stable database identifiers for inferred ancestral genes, which are used to associate inferred gene attributes with particular genes in the common ancestral genomes of extant species.
Abstract
PANTHER (Protein Analysis Through Evolutionary Relationships, http://www.pantherdb.org) is a resource for the evolutionary and functional classification of protein-coding genes from all ...domains of life. The evolutionary classification is based on a library of over 15,000 phylogenetic trees, and the functional classifications include Gene Ontology terms and pathways. Here, we analyze the current coverage of genes from genomes in different taxonomic groups, so that users can better understand what to expect when analyzing a gene list using PANTHER tools. We also describe extensive improvements to PANTHER made in the past two years. The PANTHER Protein Class ontology has been completely refactored, and 6101 PANTHER families have been manually assigned to a Protein Class, providing a high level classification of protein families and their genes. Users can access the TreeGrafter tool to add their own protein sequences to the reference phylogenetic trees in PANTHER, to infer evolutionary context as well as fine-grained annotations. We have added human enhancer-gene links that associate non-coding regions with the annotated human genes in PANTHER. We have also expanded the available services for programmatic access to PANTHER tools and data via application programming interfaces (APIs). Other improvements include additional plant genomes and an updated PANTHER GO-slim.
The PANTHER (protein annotation through evolutionary relationship) classification system (http://www.pantherdb.org/) is a comprehensive system that combines gene function, ontology, pathways and ...statistical analysis tools that enable biologists to analyze large-scale, genome-wide data from sequencing, proteomics or gene expression experiments. The system is built with 82 complete genomes organized into gene families and subfamilies, and their evolutionary relationships are captured in phylogenetic trees, multiple sequence alignments and statistical models (hidden Markov models or HMMs). Genes are classified according to their function in several different ways: families and subfamilies are annotated with ontology terms (Gene Ontology (GO) and PANTHER protein class), and sequences are assigned to PANTHER pathways. The PANTHER website includes a suite of tools that enable users to browse and query gene functions, and to analyze large-scale experimental data with a number of statistical tests. It is widely used by bench scientists, bioinformaticians, computer scientists and systems biologists. In the 2013 release of PANTHER (v.8.0), in addition to an update of the data content, we redesigned the website interface to improve both user experience and the system's analytical capability. This protocol provides a detailed description of how to analyze genome-wide experimental data with the PANTHER classification system.
Children and adolescents exhibit a broad range of clinical outcomes from SARS-CoV-2 infection, with the majority having minimal to mild symptoms. Additionally, some succumb to a severe ...hyperinflammatory post-infectious complication called multisystem inflammatory syndrome in children (MIS-C), predominantly affecting previously healthy individuals. Studies characterizing the immunological differences associated with these clinical outcomes have identified pathways important for host immunity to SARS-CoV-2 and innate modulators of disease severity. In this Review, we delineate the immunological mechanisms underlying the spectrum of pediatric immune response to SARS-CoV-2 infection in comparison with that of adults.
The PANTHER database (Protein ANalysis THrough Evolutionary Relationships, http://pantherdb.org) contains comprehensive information on the evolution and function of protein-coding genes from 104 ...completely sequenced genomes. PANTHER software tools allow users to classify new protein sequences, and to analyze gene lists obtained from large-scale genomics experiments. In the past year, major improvements include a large expansion of classification information available in PANTHER, as well as significant enhancements to the analysis tools. Protein subfamily functional classifications have more than doubled due to progress of the Gene Ontology Phylogenetic Annotation Project. For human genes (as well as a few other organisms), PANTHER now also supports enrichment analysis using pathway classifications from the Reactome resource. The gene list enrichment tools include a new 'hierarchical view' of results, enabling users to leverage the structure of the classifications/ontologies; the tools also allow users to upload genetic variant data directly, rather than requiring prior conversion to a gene list. The updated coding single-nucleotide polymorphisms (SNP) scoring tool uses an improved algorithm. The hidden Markov model (HMM) search tools now use HMMER3, dramatically reducing search times and improving accuracy of E-value statistics. Finally, the PANTHER Tree-Attribute Viewer has been implemented in JavaScript, with new views for exploring protein sequence evolution.
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