Which Hemochromatosis Mouse Model Is Best for You?: Accessing Information about Mouse Mutant Phenotypes and Their Human Disease Associations.
Authors: Onda Hiroaki , Smith Cynthia L. , Burkart Donna L. , Washburn Linda L. , Lu Ira , Bello Susan M. , Tomczuk Monika , Anagnostopoulus Anna , Cassell Megan , Eppig Janan T. 
Published: October 2019

The mouse is the premier model organism in human disease research because all of its life stages are accessible and there are myriad experimental tools for comparative analysis and specific manipulation of its genome. The Mouse Genome Informatics Database (MGI, http://www.informatics.jax.org) supports biological knowledge building for the laboratory mouse by integrating and providing access to a wide range of data from DNA sequence to phenotype and disease associations. The integration of complex disease phenotypes, underlying genetic causes, and gene function information can be used to confirm human disease models and provide insight into disease mechanisms. We will illustrate the utility of MGI using hemochromatosis as an example. To describe phenotypic abnormalities and similarities to human disease in the mouse, we developed and utilize a vocabulary of mouse anomalies (the Mammalian Phenotype Ontology) and utilize the human disease terms provided in the Online Mendelian Inheritance in Man (OMIM). These standard terms provide a backbone for annotation, allowing both easy access and searching for researchers via web forms and computational access for data downloads.

Within MGI, more than 12,000 mouse mutant alleles have been catalogued, representing mutations in more than 6,150 genes. Of these, more than 1,000 mutant alleles in 760 genes are associated with Mammalian Phenotype terms for hematopoietic defects and approximately 150 of these have an OMIM human disease association. For example, there are 26 alleles in 13 genes associated with Hermansky-Pudlak syndrome, 6 alleles in 4 genes associated with hereditary spherocytosis, and 9 alleles in 5 genes associated with hemochromatosis.

According to OMIM data, hemochromatosis in human is associated with at least 5 different genes including HFE, HFE2, HAMP, TFR2, and SLC40A1. In mouse, 12 mutant alleles in three orthologous mouse genes, Hfe, Tfr2, and Slc40a1, have been described and used as potential models for hemochromatosis. Of these mutant alleles, 6 are associated with hemochromatosis phenotypes in MGI. In addition, there are at least 6 mutant alleles in 4 additional genes (B2m, Heph, Tfrc, and Trfr2) that have been associated with the hemocromatosis phenotype in mice and may yet be discovered to influence disease in humans. Finding an appropriate model system for study of human disease is a critical step toward understanding the biological mechanism leading to disease phenotype in human and mouse. MGI provides researchers with query forms that allow simple and complex questions to be addressed. These can range from queries about a single gene or disease term to precise queries that simultaneously address phenotype, disease, gene function, expression, and genome location data. The vocabulary-based phenotype and disease annotations as well as other structured data types can assist in robust and accurate data mining when posing complex biological questions in both computational and individual formats at MGI.