Rodent Models

Rodents play an important role in biology and medicine. Since the mouse and rat share many biological characteristics with humans, they are commonly used as model organisms for understanding disease processes and testing treatments. Moreover, it is relatively easy to experimentally manipulate the genetic composition of mice and rats and, thereby, to model human genetic disorders in these animals.

Large numbers of mice can be raised quickly and relatively cost-effectively. Mice have short life spans and relatively short generation times. This makes the mouse an extremely useful experimental system for studying the genetics and biology of human disease. Rats are slightly more similar to humans than are mice, but rats are larger, have a longer generation time, are less well-characterized genetically, and are not as easily genetically manipulated. So while rats are useful in the study of some aspects of biology, mice are now much more widely used in molecular genetic research.

Many features of human biology at the cellular and molecular levels are shared with a wide variety of organisms. As mammals, the mouse and rat are highly related to humans, with similar genes, biochemical pathways, organs, and physiology.

The genomes of both human and mouse have now been sequenced, and they show striking similarity. Estimates of the total number of genes in both genomes are very comparable, ranging from 30,000 to 40,000. It is thought that only about 1 percent of human genes are unique and do not have a mouse counterpart. In addition, mouse genes are on average approximately 85 percent similar in sequence to their human counterparts. Thus, mice and humans are very highly related at the genetic level.

Before the advent of genetic modification techniques in the twentieth century, collecting mouse strains with unusual characteristics was a pastime of amateur enthusiasts. These variant strains, often showing physical characteristics such as unusual fur or tails, arose as a result of spontaneous mutations . The discovery that radiation and chemicals could increase the rate of mutation led to the development of laboratory mouse stocks, which are a useful source of genetic variation. Over 1,000 spontaneous or radiation-induced mutations have been documented, and many have been the starting point for the study of relevant human diseases and biology. For example, the cloning of the obese and diabetic mouse mutants identified the hormone leptin and its receptor, respectively, and opened up an entirely new area of research into the control of various physiological processes, including the control of body weight.

The importance of mice in genetic studies was first recognized in the related areas of immunology and cancer research, for which a mammalian model of human diseases was essential. Mice have been used in cancer research for almost a century, starting with the breeding of mouse strains susceptible to particular tumor types and, subsequently, in the induction of tumors by chemical compounds. These experiments were critical for demonstrating that the development of cancer is a multistep process, consisting of a series of genetic changes.

Although it has long been obvious that many other aspects of human biology and development can be studied using mouse models, until recently the methods for doing so did not exist. Mouse models moved to the forefront of modern biomedical research with the emergence of recombinant DNA technology, thirty years ago, and the pace has been accelerating ever since. The advent of this technology eventually culminated in the publication of the complete human genome sequence in 2001, and by 2002 the sequence and structure of almost every mouse gene will also be known. In combination with advances in DNA cloning, methods were developed for adding genes to mice (called transgenes) and removing genes (called gene targeting). These introduced genetic changes allow researchers to model human diseases by altering specific genes that are altered in particular human disease states.

For example, the mouse counterpart of atm, the gene that causes the human disease ataxia telangiectasia, was identified. In humans the symptoms of this disease include movement problems, abnormal blood vessels, immune defects, and a predisposition to cancer. The mouse atm gene was specifically disrupted by gene targeting, and mice lacking this gene exhibit a range of problems similar to those exhibited by the human patients. This mouse model is useful not only for studying and understanding the function of the gene in humans and its role in the disease process, but also for testing potential therapies.

Now that the sequencing of the human and mouse genes is completed, there is a large gap between the number of genes that have been identified and our understanding of how those genes function. The next challenge is to start to determine how those genes function in normal development and how these genes are disrupted in various disease conditions. Arguably, mouse models will become even more important during this phase of the analysis of the genome, as mice are amenable to a systematic genome-wide mutation of genes, which will allow the function of large numbers of genes to be determined.

see also Gene Targeting; Model Organisms; Recombinant DNA; Transgenic Animals.

Seth G. N. Grant

and Douglas J. C. Strathdee

Bibliography

Jackson, Ian J., and Catherine M. Abbot, eds. Mouse Genetics and Transgenics: A Practical Approach. New York: Oxford University Press, 2000.

Lyon, Mary F., Sohaila Rastan, and S. D. M. Brown. Genetic Variants and Strains of the Laboratory Mouse, 3rd ed. New York: Oxford University Press, 1996.

Rossant, Janet, and Patrick P. L. Tam, eds. Mouse Development: Patterning, Morphogenesis, and Organogenesis. San Diego: Academic Press, 2001.