The Monarch Initiative in 2024: an analytic platform integrating phenotypes, genes and diseases across species.

Bridging the gap between genetic variations, environmental determinants, and phenotypic outcomes is critical for supporting clinical diagnosis and understanding mechanisms of diseases. It requires integrating open data at a global scale. The Monarch Initiative advances these goals by developing open ontologies, semantic data models, and knowledge graphs for translational research.

The Human Phenotype Ontology in 2024: phenotypes around the world.

The Human Phenotype Ontology (HPO) is a widely used resource that comprehensively organizes and defines the phenotypic features of human disease, enabling computational inference and supporting genomic and phenotypic analyses through semantic similarity and machine learning algorithms. The HPO has widespread applications in clinical diagnostics and translational research, including genomic diagnostics, gene-disease discovery, and cohort analytics. In recent years, groups around the world have developed translations of the HPO from English to other languages, and the HPO browser has been internationalized, allowing users to view HPO term labels and in many cases synonyms and definitions in ten languages in addition to English.

KG-Hub-building and exchanging biological knowledge graphs.

Motivation: Knowledge graphs (KGs) are a powerful approach for integrating heterogeneous data and making inferences in biology and many other domains, but a coherent solution for constructing, exchanging, and facilitating the downstream use of KGs is lacking.

Results: Here we present KG-Hub, a platform that enables standardized construction, exchange, and reuse of KGs. Features include a simple, modular extract-transform-load pattern for producing graphs compliant with Biolink Model (a high-level data model for standardizing biological data), easy integration of any OBO (Open Biological and Biomedical Ontologies) ontology, cached downloads of upstream data sources, versioned and automatically updated builds with stable URLs, web-browsable storage of KG artifacts on cloud infrastructure, and easy reuse of transformed subgraphs across projects.

The Ontology of Biological Attributes (OBA)-computational traits for the life sciences.

Existing phenotype ontologies were originally developed to represent phenotypes that manifest as a character state in relation to a wild-type or other reference. However, these do not include the phenotypic trait or attribute categories required for the annotation of genome-wide association studies (GWAS), Quantitative Trait Loci (QTL) mappings or any population-focussed measurable trait data. The integration of trait and biological attribute information with an ever increasing body of chemical, environmental and biological data greatly facilitates computational analyses and it is also highly relevant to biomedical and clinical applications.

The Ontology of Biological Attributes (OBA) - Computational Traits for the Life Sciences.

Existing phenotype ontologies were originally developed to represent phenotypes that manifest as a character state in relation to a wild-type or other reference. However, these do not include the phenotypic trait or attribute categories required for the annotation of genome-wide association studies (GWAS), Quantitative Trait Loci (QTL) mappings or any population-focused measurable trait data. Moreover, variations in gene expression in response to environmental disturbances even without any genetic alterations can also be associated with particular biological attributes.

Biolink Model: A universal schema for knowledge graphs in clinical, biomedical, and translational science.

Within clinical, biomedical, and translational science, an increasing number of projects are adopting graphs for knowledge representation. Graph-based data models elucidate the interconnectedness among core biomedical concepts, enable data structures to be easily updated, and support intuitive queries, visualizations, and inference algorithms. However, knowledge discovery across these "knowledge graphs" (KGs) has remained difficult.

A Simple Standard for Sharing Ontological Mappings (SSSOM).

Despite progress in the development of standards for describing and exchanging scientific information, the lack of easy-to-use standards for mapping between different representations of the same or similar objects in different databases poses a major impediment to data integration and interoperability. Mappings often lack the metadata needed to be correctly interpreted and applied. For example, are two terms equivalent or merely related? Are they narrow or broad matches? Or are they associated in some other way? Such relationships between the mapped terms are often not documented, which leads to incorrect assumptions and makes them hard to use in scenarios that require a high degree of precision (such as diagnostics or risk prediction).

Wikidata as a knowledge graph for the life sciences.

Wikidata is a community-maintained knowledge base that has been assembled from repositories in the fields of genomics, proteomics, genetic variants, pathways, chemical compounds, and diseases, and that adheres to the FAIR principles of findability, accessibility, interoperability and reusability. Here we describe the breadth and depth of the biomedical knowledge contained within Wikidata, and discuss the open-source tools we have built to add information to Wikidata and to synchronize it with source databases. We also demonstrate several use cases for Wikidata, including the crowdsourced curation of biomedical ontologies, phenotype-based diagnosis of disease, and drug repurposing.

The Monarch Initiative in 2019: an integrative data and analytic platform connecting phenotypes to genotypes across species.

In biology and biomedicine, relating phenotypic outcomes with genetic variation and environmental factors remains a challenge: patient phenotypes may not match known diseases, candidate variants may be in genes that haven't been characterized, research organisms may not recapitulate human or veterinary diseases, environmental factors affecting disease outcomes are unknown or undocumented, and many resources must be queried to find potentially significant phenotypic associations. The Monarch Initiative (https://monarchinitiative.org) integrates information on genes, variants, genotypes, phenotypes and diseases in a variety of species, and allows powerful ontology-based search.

Demonstration of Persistent Infections and Genome Stability by Whole-Genome Sequencing of Repeat-Positive, Same-Serovar Chlamydia trachomatis Collected From the Female Genital Tract.

Background: The biology of recurrent or long-term infections of humans by Chlamydia trachomatis is poorly understood. Because repeated or persistent infections are correlated with serious complications in humans, understanding these processes may improve clinical management and public health disease control.

Methods: We conducted whole-genome sequence analysis on C.

WikiGenomes: an open web application for community consumption and curation of gene annotation data in Wikidata.

Unlabelled: With the advancement of genome-sequencing technologies, new genomes are being sequenced daily. Although these sequences are deposited in publicly available data warehouses, their functional and genomic annotations (beyond genes which are predicted automatically) mostly reside in the text of primary publications. Professional curators are hard at work extracting those annotations from the literature for the most studied organisms and depositing them in structured databases.

Beyond Tryptophan Synthase: Identification of Genes That Contribute to Chlamydia trachomatis Survival during Gamma Interferon-Induced Persistence and Reactivation.

Chlamydia trachomatis can enter a viable but nonculturable state in vitro termed persistence. A common feature of C. trachomatis persistence models is that reticulate bodies fail to divide and make few infectious progeny until the persistence-inducing stressor is removed.

Interrogating Genes That Mediate Chlamydia trachomatis Survival in Cell Culture Using Conditional Mutants and Recombination.

Unlabelled: Intracellular bacterial pathogens in the family Chlamydiaceae are causes of human blindness, sexually transmitted disease, and pneumonia. Genetic dissection of the mechanisms of chlamydial pathogenicity has been hindered by multiple limitations, including the inability to inactivate genes that would prevent the production of elementary bodies. Many genes are also Chlamydia-specific genes, and chlamydial genomes have undergone extensive reductive evolution, so functions often cannot be inferred from homologs in other organisms.

High-performance web services for querying gene and variant annotation.

Efficient tools for data management and integration are essential for many aspects of high-throughput biology. In particular, annotations of genes and human genetic variants are commonly used but highly fragmented across many resources. Here, we describe MyGene.

Centralizing content and distributing labor: a community model for curating the very long tail of microbial genomes.

The last 20 years of advancement in sequencing technologies have led to sequencing thousands of microbial genomes, creating mountains of genetic data. While efficiency in generating the data improves almost daily, applying meaningful relationships between taxonomic and genetic entities on this scale requires a structured and integrative approach. Currently, knowledge is distributed across a fragmented landscape of resources from government-funded institutions such as National Center for Biotechnology Information (NCBI) and UniProt to topic-focused databases like the ODB3 database of prokaryotic operons, to the supplemental table of a primary publication.

Wikidata as a semantic framework for the Gene Wiki initiative.

Open biological data are distributed over many resources making them challenging to integrate, to update and to disseminate quickly. Wikidata is a growing, open community database which can serve this purpose and also provides tight integration with Wikipedia. In order to improve the state of biological data, facilitate data management and dissemination, we imported all human and mouse genes, and all human and mouse proteins into Wikidata.

Application of a nanoflare probe specific to a latency associated transcript for isolation of KHV latently infected cells.

One of the unique features of herpesvirus infection is latent infection following an initial exposure, which is characterized by viral genome persistence in a small fraction of cells within the latently infected tissue. Investigation of the mechanisms of herpesvirus latency has been very challenging in tissues with only a small fraction of cells that are latently infected. Cyprinid herpesvirus 3, also known as koi herpesvirus (KHV), is an important and deadly pathogen of koi and common carp, Cyprinus carpio.

Culture-independent sequence analysis of Chlamydia trachomatis in urogenital specimens identifies regions of recombination and in-patient sequence mutations.

A culture-independent genome sequencing approach was developed and used to examine genomic variability in Chlamydia trachomatis-positive specimens that were collected from patients in the Seattle, WA, USA, area. The procedure is based on an immunomagnetic separation approach with chlamydial LPS-specific mAbs, followed by DNA purification and total DNA amplification, and subsequent Illumina-based sequence analysis. Quality of genome sequencing was independent of the total number of inclusion-forming units determined for the sample and the amount of non-chlamydial DNA in the Illumina libraries.

Sequence and comparative analysis of the genome of HSV-1 strain McKrae.

Ocular infection by HSV-1 strain McKrae is neurovirulent in both mice and rabbits and causes fatal encephalitis in approximately 50% of animals. In addition, it spontaneously reactivates with high frequency relative to other HSV-1 strains in rabbits. We sequenced the McKrae strain genome and compared its coding protein sequences with those of six other HSV-1 strains.

Resistance to a novel antichlamydial compound is mediated through mutations in Chlamydia trachomatis secY.

A novel and quantitative high-throughput screening approach was explored as a tool for the identification of novel compounds that inhibit chlamydial growth in mammalian cells. The assay is based on accumulation of a fluorescent marker by intracellular chlamydiae. Its utility was demonstrated by screening 42,000 chemically defined compounds against Chlamydia caviae GPIC.

Irinotecan and gemcitabine in patients with solid tumors: phase I trial.

Using a day 1 and 8, every-3-week schedule, our purpose was to determine the maximum tolerated dose of irinotecan (CPT-11, Camptosar) that can be administered immediately after gemcitabine (Gemzar) at a dose of 1,000 mg/m2 IV. In this phase I trial, the maximum tolerated dose was defined as the dose level immediately below the level in which two of the first three patients in any cohort, or at least two of six patients in any expanded cohort, experienced dose-limiting toxicity. Dose-limiting toxicity pertained only to toxicity during the first cycle of treatment.

Single-agent gemcitabine and gemcitabine/irinotecan combination (irimogem) in non-small cell lung cancer.

Gemcitabine is a fluoridated pyrimidine related to cytosine arabinoside that has significant activity in solid tumor models. Irinotecan is a camptothecin analog with an active metabolite, SN-38, which inhibits topoisomerase I activity by stabilizing the topoisomerase I-DNA cleavable complex. Gemcitabine studies in non-small cell lung cancer conducted in the United States, as well as an international collaboration and clinical trials from Europe and Japan, found overall response rates of 20% to 26%, a median duration of response between 5 to 9 months, and a median duration of survival ranging from 7 to 12.