Building a molecular glyco-phenotype ontology to decipher undiagnosed diseases

Abstract-Hundreds of rare diseases are due to mutation on genes related to glycans synthesis, degradation or recognition. These glycan-related defects are well described in the literature but largely absent in ontologies and databases of chemical entities and phenotypes, limiting the application of computational methods and ontology-driven tools for characterization and discovery of glycan related diseases. We are curating articles and textbooks in glycobiology related to genetic diseases to inform the content and the structure of an ontology of Molecular GlycoPhenotypes (MGPO). MGPO will be applied toward use cases including disease diagnosis and disease gene candidate prioritization, using semantic similarity and pattern matching at the glycan level with glycomics data from patient of the Undiagnosed Diseases Network

Significantly different clinical phenotypes associated with mutations in synthesis and transamidase+remodeling glycosylphosphatidylinositol (GPI)-anchor biosynthesis genes.

BACKGROUND: Defects in the glycosylphosphatidylinositol (GPI) biosynthesis pathway can result in a group of congenital disorders of glycosylation known as the inherited GPI deficiencies (IGDs). To date, defects in 22 of the 29 genes in the GPI biosynthesis pathway have been identified in IGDs. The early phase of the biosynthetic pathway assembles the GPI anchor (Synthesis stage) and the late phase transfers the GPI anchor to a nascent peptide in the endoplasmic reticulum (ER) (Transamidase stage), stabilizes the anchor in the ER membrane using fatty acid remodeling and then traffics the GPI-anchored protein to the cell surface (Remodeling stage). RESULTS: We addressed the hypothesis that disease-associated variants in either the Synthesis stage or Transamidase+Remodeling-stage GPI pathway genes have distinct phenotypic spectra. We reviewed clinical data from 58 publications describing 152 individual patients and encoded the phenotypic information using the Human Phenotype Ontology (HPO). We showed statistically significant differences between the Synthesis and Transamidase+Remodeling Groups in the frequencies of phenotypes in the musculoskeletal system, cleft palate, nose phenotypes, and cognitive disability. Finally, we hypothesized that phenotypic defects in the IGDs are likely to be at least partially related to defective GPI anchoring of their target proteins. Twenty-two of one hundred forty-two proteins that receive a GPI anchor are associated with one or more Mendelian diseases and 12 show some phenotypic overlap with the IGDs, represented by 34 HPO terms. Interestingly, GPC3 and GPC6, members of the glypican family of heparan sulfate proteoglycans bound to the plasma membrane through a covalent GPI linkage, are associated with 25 of these phenotypic abnormalities. CONCLUSIONS: IGDs associated with Synthesis and Transamidase+Remodeling stages of the GPI biosynthesis pathway have significantly different phenotypic spectra. GPC2 and GPC6 genes may represent a GPI target of general disruption to the GPI biosynthesis pathway that contributes to the phenotypes of some IGDs

Representing glycophenotypes: semantic unification of glycobiology resources for disease discovery.

While abnormalities related to carbohydrates (glycans) are frequent for patients with rare and undiagnosed diseases as well as in many common diseases, these glycan-related phenotypes (glycophenotypes) are not well represented in knowledge bases (KBs). If glycan-related diseases were more robustly represented and curated with glycophenotypes, these could be used for molecular phenotyping to help to realize the goals of precision medicine. Diagnosis of rare diseases by computational cross-species comparison of genotype-phenotype data has been facilitated by leveraging ontological representations of clinical phenotypes, using Human Phenotype Ontology (HPO), and model organism ontologies such as Mammalian Phenotype Ontology (MP) in the context of the Monarch Initiative. In this article, we discuss the importance and complexity of glycobiology and review the structure of glycan-related content from existing KBs and biological ontologies. We show how semantically structuring knowledge about the annotation of glycophenotypes could enhance disease diagnosis, and propose a solution to integrate glycophenotypes and related diseases into the Unified Phenotype Ontology (uPheno), HPO, Monarch and other KBs. We encourage the community to practice good identifier hygiene for glycans in support of semantic analysis, and clinicians to add glycomics to their diagnostic analyses of rare diseases

Forming consensus to advance urobiome research

Urobiome research has the potential to advance the understanding of a wide range of diseases, including lower urinary tract symptoms and kidney disease. Many scientific areas have benefited from early research method consensus to facilitate the greater, common good. This consensus document, developed by a group of expert investigators currently engaged in urobiome research (UROBIOME 2020 conference participants), aims to promote standardization and advances in this field by the adoption of common core research practices. We propose a standardized nomenclature as well as considerations for specimen collection, preservation, storage, and processing. Best practices for urobiome study design include our proposal for standard metadata elements as part of core metadata collection. Although it is impractical to follow fixed analytical procedures when analyzing urobiome data, we propose guidelines to document and report data originating from urobiome studies. We offer this first consensus document with every expectation of subsequent revision as our field progresses

Expansion of the Human Phenotype Ontology (HPO) knowledge base and resources.

The Human Phenotype Ontology (HPO)-a standardized vocabulary of phenotypic abnormalities associated with 7000+ diseases-is used by thousands of researchers, clinicians, informaticians and electronic health record systems around the world. Its detailed descriptions of clinical abnormalities and computable disease definitions have made HPO the de facto standard for deep phenotyping in the field of rare disease. The HPO\u27s interoperability with other ontologies has enabled it to be used to improve diagnostic accuracy by incorporating model organism data. It also plays a key role in the popular Exomiser tool, which identifies potential disease-causing variants from whole-exome or whole-genome sequencing data. Since the HPO was first introduced in 2008, its users have become both more numerous and more diverse. To meet these emerging needs, the project has added new content, language translations, mappings and computational tooling, as well as integrations with external community data. The HPO continues to collaborate with clinical adopters to improve specific areas of the ontology and extend standardized disease descriptions. The newly redesigned HPO website (www.human-phenotype-ontology.org) simplifies browsing terms and exploring clinical features, diseases, and human genes

Ancient Egyptian Genomes from northern Egypt: Further discussion

Schuenemann et al.1 seemingly suggest, based largely on the results of an ancient DNA study of later period remains from northern Egypt, that the ‘ancient Egyptians’ (AE) as an entity came from Asia (the Near East, NE), and that modern Egyptians “received additional sub-Saharan African (SSA) admixtures in recent times” after the latest period of the pharaonic era due to the “trans-Saharan slave trade and Islamic expansion.” In spite of the implied generalization about ‘origins’ the authors do offer the caveat that their findings may have been different if samples had been used from southern Egypt, and this is a significant admission. Their conclusions deserve further discussion from multiple perspectives which cannot be fully developed due to space limitations. There are alternative interpretations of the results but which were not presented as is traditionally done, with the exception of the admission that results from southern Egyptians may have been different. The alternative interpretations involve three major considerations: 1) sampling and methodology, 2) historiography and 3) definitions as they relate to populations, origins and evolution

Alain Anselin (1943-2019), d’une rive à l’autre, de la Caraïbe à l’Égypte

Gourdine Jean-Philippe, Silpa Fabrice, Anselin Osendé. Alain Anselin (1943-2019), d’une rive à l’autre, de la Caraïbe à l’Égypte. In: Archéo-Nil. Revue de la société pour l'étude des cultures prépharaoniques de la vallée du Nil, n°29, 2019. Égypte et Afrique. Une civilisation africaine ? pp. 15-20

High Affinity Interaction between a Bivalve C-type Lectin and a Biantennary Complex-type N -Glycan Revealed by Crystallography and Microcalorimetry

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