With completion of the first draft of the human and mouse genomic sequences, there is increased emphasis in identifying the function and interaction of the full set of genes in normal and pathologic metabolism. Also, because of the extensive synteny between mouse and human genomes, the large number of well characterized inbred mouse strains and the largely similar metabolism between mammalian species, it is now widely recognized that the mouse, as an animal model, will play an important role in mapping genes important to human disease and in testing the physiologic roles of these genes, once identified.
Much of the work to identify novel genes associated with complex diseases
has been carried out by quantitative trait locus (QTL) mapping, an approach
that attempts to statistically link inheritance of disease-related phenotypes
with parental origins of DNA in any given chromosomal region. While
QTL mapping has been successful at identifying broad genetic loci, attempts
to more finely localize the underlying genes have been less fruitful.
The basic QTL-linkage approach applied to complex traits has not had the
statistical power to resolve specific genes in outbred populations or even
in crosses between inbred strains of mice. Thus, it is widely recognized
that alternative approaches are required in the quest to identify and characterize
the particular responsible gene within a QTL
One of the most powerful tools in this effort is the congenic mouse. These mice are derived from two inbred mouse strains, a donor strain and a background strain. The congenic mouse carries only DNA from the background strain except in a single small region previously identified as biologically important. At this locus, the congenic carries DNA from the donor strain, usually selected because the donor and background strains are known to diverge genetically in a manner that alters normal metabolism or disease susceptibility. It is not necessary to know the underlying gene and, in fact, the congenic mouse is the ideal tool to test the impact of the locus and to narrow the locus in an effort to isolate the responsible gene.
While many researchers recognize the great utility of congenic strains to accelerate analysis of complex traits, it is both expensive and time consuming to construct congenics specific to a particular gene locus. In recognition of this, Aldons J. Lusis, initiated a project to develop a full set of congenics spanning the mouse genome. This project is now developed to the point where all the desired congenic regions have been identified and isolated. Thus, we now have available two “libraries” of congenic animals with a set of introgressed segments covering all 19 autosomes and the X chromosome. Each of these libraries, that we call genome tagged mice (GTM), is comprised of more than 60 individual congenic strains. Both libraries use C57BL/6J as the background strain. The introgressed segments come either from DBA/2J (DBA-GTM library) or CAST/Ei (CAST-GTM library). Due to the small size of the introgressed chromosomal segment, GTMs allow direct initiation of positional cloning projects, as well as the resolution of multiple QTLs that may be present on a chromosome. They also greatly facilitate the direct mapping of QTLs and the analysis of gene-gene interactions.
We are now completing breeding to produce stable homozygous lines for the GTM strains and will make these strains generally available. Many researchers are poised to take immediate advantage of this resource. Their research, funded by a broad spectrum of institutes within the NIH, aims to identify genes underlying complex diseases including alcoholism, obesity, drug dependence, cancer, rheumatoid arthritis, glaucoma, atherosclerosis, osteoporosis and others. The GTM resource provides an exciting new avenue for all of these projects, facilitating the rapid characterization of disease-related genes, a process that otherwise would require great expense and years of effort.
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