Mouse models of human diseases

The value of the mouse as a model for human disease has become firmly established as new mutants are repeatedly validated as models of human disease and, increasingly, the similarities in the pathobiology of the two species provide new insights into disease mechanisms and aetiologies (Peters et al., 2007; Rosenthal and Brown, 2007; Justice, 2008; Brown et al., 2009). Mutant strains derived from hypothesis-driven research are now being augmented by large-scale mutagenesis efforts that are being undertaken worldwide (Brown et al., 2009). Following the successful phenotype-driven N-ethyl-N-nitrosourea (ENU) mutagenesis projects, the products of which are still being analyzed, large-scale gene knockout programmes have been established to provide the mutant embryonic stem (ES) cells and mice that are needed to discover the functions of all of the protein-coding genes in the mouse genome. The International Knockout Mouse Consortium, (IKMC; www.knockoutmouse.org) (International Mouse Knockout Consortium et al., 2007), composed of four international partners (EUCOMM, KOMP, NorCOMM and TIGM), is currently producing large collections of targeted and gene-trapped mouse mutants. Currently 13,374 genes have been knocked out from a target number close to 24,000. More than 500 mouse lines are expected to be systematically phenotyped within the next five years using standardised phenotyping procedures developed by the EUMORPHIA (European Union Mouse Research for Public Health and Industrial Applications) and EUMODIC (The European Mouse Disease Clinics) consortia (www.eumodic.org) (Brown et al., 2005). The mutagenesis efforts are not the only new sources of large amounts of systematic phenotyping data. The Shock-Ellison Medical Foundation-funded mouse aging programme at the Jackson Laboratory (http://agingmice.jax.org/index.html) is keeping mice from 31 different strains for the entirety of their natural life span to generate a huge volume of age-dependent phenotype data covering physiology, pathology and gene expression (Yuan et al., 2009). Longitudinal, cross-sectional and targeted studies of these mice provide interesting insights into the pathophysiology of aging. By using the high-resolution single nucleotide polymorphism (SNP) maps that are now available, these data will generate new gene/phenotype associations for many age-related conditions and complex traits. To make the best use of the sheer volume and depth of the emerging mouse phenotype data we need to be able to relate it to human ‘phenotype’ or disease data in a way that is amenable to computation; it is this challenge that we discuss here.