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.
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.