Abstract

The mouse, as a prototypical mammal, has been the subject of systematic experimental investigation for the last century. An ever-enlarging number of mouse mutations exist that provide models for human genetic disorders, and the mouse has become an increasingly important tool for dissecting the molecular basis of common acquired disease states. The most frequently used approaches to modifying the mouse genome are microinjection of purified DNA and homologous recombination in embryonic stem cells.

The laboratory mouse provides a number of advantages as an experimental system. It is small and hence inexpensive to keep under well-controlled environmental conditions. Mice produce abundant offspring following a short gestation, allowing for large sample sizes, and there exist numerous inbred strains available for selective breeding strategies. The mouse shares many metabolic and developmental pathways with humans, and there are syntenic relationships over much of its genome that correspond to those of humans. Numerous reagents exist for gene mapping and identification, and because of historic interests, there are frequently multiple alleles at a given locus. Complex genetic interactions can be examined using selected compound alleles, double mutations, and strain-specific modifiers. Genetic mechanisms such as haploinsufficiency,¹digenic inheritance,²and imprinting,^3,4can be experimentally dissected in the mouse.

Mice can also be used as recipients for human tissues such as bone marrow, and can be genetically “humanized” via the introduction of human alleles, whether disease associated or conferring disease resistance. This may represent single genes or more recently large regions of DNA, and even chromosomal fragments. The development of standardized behavioral testing and an ever-expanding understanding of mouse behavior has provided a means for defining the genetic and molecular basis of learning and memory, an increasingly achievable goal for the future. The mouse is also a unique resource for the development of phenotype driven genetic screens for mutant genes when mutagenesis is coupled to a standardized battery of assessments such as behavioral, sensory, biochemical, and physiological testing.

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