Disease model discovery from 3,328 gene knockouts by The International Mouse Phenotyping Consortium.

Although next-generation sequencing has revolutionized the ability to associate variants with human diseases, diagnostic rates and development of new therapies are still limited by a lack of knowledge of the functions and pathobiological mechanisms of most genes. To address this challenge, the International Mouse Phenotyping Consortium is creating a genome- and phenome-wide catalog of gene function by characterizing new knockout-mouse strains across diverse biological systems through a broad set of standardized phenotyping tests. All mice will be readily available to the biomedical community. Analyzing the first 3,328 genes identified models for 360 diseases, including the first models, to our knowledge, for type C Bernard-Soulier, Bardet-Biedl-5 and Gordon Holmes syndromes. 90% of our phenotype annotations were novel, providing functional evidence for 1,092 genes and candidates in genetically uncharacterized diseases including arrhythmogenic right ventricular dysplasia 3. Finally, we describe our role in variant functional validation with The 100,000 Genomes Project and others.

The Pitfalls of Thesaurus Ontologization - the Case of the NCI Thesaurus.

Thesauri that are "ontologized" into OWL-DL semantics are highly amenable to modeling errors resulting from falsely interpreting existential restrictions. We investigated the OWL-DL representation of the NCI Thesaurus (NCIT) in order to assess the correctness of existential restrictions. A random sample of 354 axioms using the someValuesFrom operator was taken. According to a rating performed by two domain experts, roughly half of these examples, and in consequence more than 76,000 axioms in the OWL-DL version, make incorrect assertions if interpreted according to description logics semantics. These axioms therefore constitute a huge source for unintended models, rendering most logic-based reasoning unreliable. After identifying typical error patterns we discuss some possible improvements. Our recommendation is to either amend the problematic axioms in the OWL-DL formalization or to consider some less strict representational format.