Recent advances in genomic research in humans and mice have reinforced the mouse as a model genetic system. They have closely related genomes of approximately the same size (about 3,000 Mb) and probably diverged from a common ancestor 80 million years ago. Counterparts of most human genes can be found in the mouse. In terms of the genomic structure, large segments of chromosomes containing the rank order of hundreds to thousands of genes have been preserved virtually intact (synteny) between the mouse and human, facilitating the application of forward and reverse genetic techniques. Laboratory mice present a vast resource of defined genetic strains, including inbred and recombinant inbred strains with characterized allelic differences that can serve as models for human genetic polymorphisms. There is a growing resource of naturally occurring and induced mutants (including a large variety of knock-out null mutants) that are commercially available, easily obtained, and easily maintained. Furthermore, the embryos of mice are accessible to embryological and genetic manipulation and have been widely used in the development of transgenic technologies.

Transgenic Technologies

Manipulating the mammalian genome has become a commonplace experimental procedure during the past two decades, and transgenic animals have been widely used in many research areas. “Transgenic” is a term that was originally coined to describe animals that had a foreign or “trans” gene inserted at random into their genome by experimental means. Its use has been broadened as more sophisticated techniques for altering the genome have been developed, and it can now be used to include any animal whose genome has been altered by addition of genetic material or by alteration of existing genes by gene targeting. Transgenic techniques, which were first devised in the 1975-1985 period, have been applied to a variety of experimental animals and agricultural animals, although by far the most common mammalian subject of gene manipulation remains the laboratory mouse.

The transgenic approach, whereby genes can be isolated, altered, and then returned to the animal, has provided a new means to investigate experimentally the function of genes and their regulation in different tissues and at different times during development. As it became clear that foreign genes could indeed function after insertion into the genome of a host, and that transgene expression was, to some extent, under experimental control, the practical uses of transgenic animals began to emerge, including uses in toxicology.

Although the first successful transgenics were made using a viral vector to deliver DNA to mammalian embryos through viral infection, the direct microinjection of cloned genes into the pronucleus (haploid nucleus) of a fertilized egg has proved to be the more versatile method and has been used widely. The principle is simple: a gene of interest is cloned, with or without regulatory elements, and is microinjected into the pronucleus. One or more copies of the gene will



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