The mouse is an excellent translational model for human disease research, providing rich phenotype-to-genotype data for studying disease mechanism, as well as evoking candidate genes for human diseases and suggesting new mutant model development in mice. Mouse Genome Informatics (MGI, www.informatics.jax.org), has developed the Human-Mouse:Disease Connection (HMDC, www.diseasemodel.org) portal for improved access to and visualization of these data. Search results in the HMDC are displayed in interactive grids and tables that are dynamically linked to MGI data such as detailed gene and phenotype information, pertinent disease model references, and available mouse model resources through repositories via the International Mouse Strain Resource (IMSR). Here we use human Myelodysplastic Syndrome (MDS) as an example of how MGI search tools aid in identifying available mouse models of human disease, quickly provide access to information on genes known to cause the disease, and identify human candidate disease genes and possible treatment targets.
MDS is a group of hematopoietic disorders in which the bone marrow does not produce sufficient blood cells. To identify experimental mouse models of MDS, investigators can search for disease terms in the HMDC. The results of a search on 'Myelodysplastic Syndrome' show that mutations in the ASXL1 human gene are implicated in MDS and that mutations in the Asxl1 mouse homolog show analogous symptoms. This model may be explored for possible therapy targets. The table indicates seven other mouse genes (Atg7, Bap1, Crebbp, Mybl2, Polq, Samd9l, Srsf2) with mutations that are reported as MDS models that are not yet associated with the human ortholog as causative genes of the disease in human and may be new potential candidate disease genes. Three human genes (GATA2, SF3B1, TET2) are implicated in this condition in which orthologous mouse mutants have not yet been reported to model this syndrome. Mutations targeting these mouse genes may be interesting to evaluate as potential murine disease models. In addition, the Phenotypes and Alleles Query form can be used to search by phenotypic terms, such as 'abnormal myelopoiesis' and 'anemia' to obtain a comprehensive list of mutant mouse alleles presenting phenotypes similar to human disease symptoms.
Coming in August 2016, the HMDC will see some exciting changes, including a simplified query form and the incorporation of the Human Phenotype Ontology so that mouse phenotypes can be more directly compared with human disease phenotypes, allowing for easier translation between mouse and human data. Supported by NHGRI grant HG000330.