ZEBRAFISH CORE The goal of the Zebrafish Core of the Model Organism Screening Center (MOSC) at the University of Oregon (UO) is to provide useful in vivo functional information and validation of candidate gene variants that are likely to underlie specific pathological phenotypes of Undiagnosed Disease Network (UDN) patients. This process will facilitate the diagnosis and development of therapies for rare diseases identified by the UDN. To provide functional information about genes in vivo, the Zebrafish Core will combine novel strategies and technologies in an innovative pipeline for high throughput analysis of candidate genes. Human genes will undergo stringent analyses to identify their zebrafish orthologs unambiguously. Then a set of bioinformatic tools, developed in collaboration with ZFIN, the zebrafish model organism data at the UO, will be used to compare the UDN patient phenotypes to known zebrafish and mouse gene expression patterns and mutant phenotypes. In some cases, this analysis will provide sufficient evidence to implicate the UDN gene as causative of the human disease. For genes with uninformative expression and/or phenotypes, the Core will generate mutants by CRISPR/Cas9 genome editing or obtain mutants from existing collections, facilitated by the close association of the Zebrafish Core to the Zebrafish International Resource Center (ZIRC), also at the UO. The Core will then analyze the phenotypes of these uncharacterized mutants and validate the candidate genes as disease- causing variants by rescue of the zebrafish mutants with human sequences. All data will be shared with the UDN sites and centers through the MOSC Leadership; all genetic resources will be openly distributed to the research community through the ZIRC; and data will be shared with the research community via ZFIN. This innovative pipeline will identify the cellular and organismal roles of UDN genes in a vertebrate with organs and organ systems that function like human organs, thus providing diagnostic information for the UDN patients, as well as evaluating the roles of these genes in human pathology.
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