The human genome is not so very different from that of chimpanzees or mice, and it even shares many common elements with the genome of the lowly fruit fly. Obviously, the differences are critical, but so are the similarities. In particular, genetic experiments on other organisms can illuminate much that we could not otherwise learn about homologous human genes -- that is, genes that are basically the same in the two species.

In some cases, the connection between a newly identified human gene and a known health disorder can be quickly established. More often, however, clear links between cloned genes and human hereditary diseases or disease susceptibilities are extremely elusive. Diseases that are modified by other genetic predispositions, for example, or by environment, diet, and lifestyle can be exceedingly difficult to trace in human families. The same holds for very rare diseases and for genetic factors contributing to birth defects and other developmental disorders. By contrast, disorders such as these can sometimes be followed relatively easily in animal systems, where uniform genetic backgrounds and controlled breeding schemes can be used to avoid the variability that often confounds human population studies. As a consequence, researchers looking for clues to the causes of many complex health problems are focusing more and more attention on model animal systems.

Among such systems, which range in complexity from yeast and bacteria to mammals, the most prominent is the mouse. Because of its small size, high fertility rate, and experimental manipulability, the mouse offers great promise in studying the genetic causes and pathological progress of ailments, as well as understanding the genetic role in disease susceptibility. In pursuing such studies, the DOE is exploiting several resources, among them the experimental mouse genetics facility at the Oak Ridge National Laboratory. Initially established for genetic risk assessment and toxicology studies, the Oak Ridge facility is one of the world's largest. Mutant strains there express a variety of inherited developmental and health disorders, ranging from dwarfism and limb deformities to sickle cell anemia, atherosclerosis, and unusual susceptibilities to cancer.

Most of these existing mutant strains have arisen from random alterations of genes, caused by the same processes that occur naturally in all living populations. However, other, more directed means of gene alteration are also available. So-called transgenic methods, which have been developed and refined over the past 15 years, allow DNA sequences engineered in the laboratory to be introduced directly into the genomes of mouse embryos. The embryos are subsequently transferred to a foster mother, where they develop into mice carrying specifically designed alterations in a particular gene. The differences in form, basic health, fertility, and longevity produced by these "designer mutations" then allow researchers to study the effects of genetic defects that can mimic those found in human patients. The payoff can be clues that aid in the design of drugs and other treatments for the human diseases.

The Human Genome Center at Berkeley is using mice for similar purposes. In vivo libraries of overlapping human genome fragments (each 100,000 to 1,000,000 base pairs long) are being propagated in transgenic mice. The region of chromosome 21 responsible for Down syndrome, for example, is now almost fully represented in a panel of transgenic mice. Such libraries have several uses. For example, the precise biochemical means by which identified genes produce their effects can be studied in detail, and new genes can be recognized by analyzing the effects of particular genome fragments on the transgenic animals. In such ways, the promise of the massive effort to map and sequence the human genome can be translated into the kind of biological knowledge coveted by pharmaceutical designers and medical researchers.

Of mice and men (36k GIF)

Adding to the potential value of mutant mice as models for human genetic disease is growing evidence of similarities between mouse and human genes. Indeed, practically every human gene appears to have a counterpart in the mouse genome. Furthermore, the related mouse and human genes often share very similar DNA sequences and the same basic biological function. If we imagine that the 23 pairs of human chromosomes were shattered into smaller blocks -- to yield a total of, say, 150 pieces, ranging in size from very small bits containing just a few genes to whole chromosome arms -- those pieces could be reassembled to produce a serviceable model of the mouse genome. This mouse genome jigsaw puzzle is shown to the right. Thanks to this mouse-human genomic homology, a newly located gene on a human chromosome can often lead to a confident prediction of where a closely related gene will be found in the mouse -- and vice versa.

Thus, a crippling heritable muscle disorder in mice maps to a location on the mouse X chromosome that is closely analogous to the map location for the X-linked human Duchenne muscular dystrophy gene (DMD). Indeed, we now know that these two similar diseases are caused by the mouse and human versions of the same gene. Although mutations in the mouse mdx gene produce a muscle disease that is less severe than the heartbreaking, fatal disease resulting from the DMD mutation in humans, the two genes produce proteins that function in very similar ways and that are clearly required for normal muscle development and function in the corresponding species. Likewise, the discovery of a mouse gene associated with pigmentation, reproductive, and blood cell defects was the crucial key to uncovering the basis for a human disease known as the piebald trait. Owing to such close human-mouse relationships as these, together with the benefits of transgenic technologies, the mouse offers enormous potential in identifying new human genes, deciphering their complex functions, and even treating genetic diseases.

To Know Ourselves was prepared at the request of the U.S. Department of Energy, Office of Health and Environmental Research, as an overview of the Human Genome Project.