The expanding role of mouse genetics for understanding human biology and disease

Abstract

It has taken about 100 years since the mouse first captured our imagination as an intriguing animal for it to become the premier genetic model organism. An expanding repertoire of genetic technology, together with sequencing of the genome and biological conservation, place the mouse at the foremost position as a model to decipher mechanisms underlying biological and disease processes. The combined approaches of embryonic stem cell-based technologies, chemical and insertional mutagenesis have enabled the systematic interrogation of the mouse genome with the aim of creating, for the first time, a library of mutants in which every gene is disrupted. The hope is that phenotyping the mutants will reveal novel and interesting phenotypes that correlate with genes, to define the first functional map of a mammalian genome. This new milestone will have a great impact on our understanding of mammalian biology, and could significantly change the future of medical diagnosis and therapeutic development, where databases can be queried in silico for potential drug targets or underlying genetic causes of illnesses. Emerging innovative genetic strategies, such as somatic genetics, modifier screens and humanized mice, in combination with whole-genome mutagenesis will dramatically broaden the utility of the mouse. More significantly, allowing genome-wide genetic interrogations in the laboratory, will liberate the creativity of individual investigators and transform the mouse as a model for making original discoveries and establishing novel paradigms for understanding human biology and disease.

Fig. 1. A functional map for the mammalian genome

The combined approaches of knockout techniques, ENU mutagenesis and insertional mutagenesis enable the research community to produce a library of mouse strains in which every gene in the genome is mutated (right panel). Systematic phenotyping of these mutants (middle panel) could identify many disease genes and establish causative relationships to produce the first functional map of a mammalian genome. Such a functional map would not only advance our understanding of human biology and disease, but also allow investigators to query the results of a patient’s diagnosis (left panel) for possible underlying genetic causes of illness and to identify possible targets for medical treatment. Diagnostic photos courtesy of Yale School of Medicine.

Fig. 2. Genetic screens in mosaic animals

Since mouse tissues contain millions of cells, hundreds or even thousands of somatic clones bearing different mutations can be produced in a single mouse (right), rather than tens of thousands of individual mice (left). Genome-wide genetic screens can therefore be conducted by individual investigators in as few as ten to several hundred mice. Several techniques are now being developed to produce a high frequency of mosaic mutant clones in the mouse, including transposon insertional mutagenesis and Cre/loxP- and FLP/FRT-mediated mitotic recombination between homologous chromosomes. Such a mosaic system for genome-wide genetic interrogation will empower investigators to explore novel and risky ideas in a mammal in individual laboratories.

Fig. 3. Database and virtual modifier screens for identifying therapeutic targets

(A) A genetic modifier screen can be performed to search for mouse mutants that can ameliorate a disease phenotype, such as mice with Ras^V12-induced tumors. The examination of gene expression profiles for every mutant permits the establishment of a mutant gene expression profile database (MEPD). Such a database would allow one to perform virtual modifier screens to identify candidate mutants, which can completely or partially revert the gene expression profile change caused by a disease condition (B). The small number of identified candidate mutants can then be tested for their ability to suppress the disease phenotype in animal experiments. The MEPD will have universal appeal for identifying potential therapeutic targets and will significantly change the current practice of drug development.