Understanding the human condition: experimental strategies in mammalian genetics

Mice have become the mammalian model of choice for the application of genetics in biomedical research due to the evolutionary conservation of physiological systems and their attendant pathologies among all mammals as well as the exceptional power of genetic research technologies in the species. Beginning from aberrant phenotypes, a large number of mouse mutants and natural polymorphisms have been cloned, providing much information about the molecular basis of physiological processes. Additionally, the variable expression of these mutations in different inbred strain backgrounds has demonstrated the importance of modifier genes, which are also susceptible to cloning. Research efforts are keeping pace with these developments. In the area of gene discovery, large, government-funded mutagenesis programs now exist, and as a matter of great practical importance, recent evidence suggests that the same genes may be involved in the natural polymorphisms affecting disease in mice and humans. In parallel, dramatic advances are also being made in our ability to measure physiological processes in mice, and the advent of expression profiling promises revolutionary advances in understanding phenotype at the molecular level. Gene-driven approaches have relied on engineering the mouse genome, including adding, subtracting, and replacing genes and, most recently, the ability to control gene activity reversibly. Together, these multiple advances in our technical abilities have created extraordinary opportunities for future discovery.