Computational Biology 11
system. However, two orthogonal approaches can be simultaneously
applied to investigate a complex biological problem. Although each
approach may have its own inherent limitations, the integrated use of
data arising from each of the two separate approaches can provide a
more efficient and precise analysis. The integrated use of gene
expression data obtained with high-density oligonucleotide microarrays
in conjunction with the SNP genotyping method has been shown to
accelerate QTL analysis (27,30,31). The identification of a genetic locus
within a defined genetic interval is accelerated by analysis of
differentially expressed genes within the region in selected tissues
obtained from the parental strains. Acomputational method for
performing genetic analysis will be described in this book. This
computational method enables candidate chromosomal regions and
specific genes to be identified very quickly for phenotypes that differ
among inbred mouse strains. If so, databases with tissuespecific gene
expression and phenotypic information across mouse strains could be
used in conjunction with the murine SNP database to computationally
identify candidate disease genes. In a hypothetical experiment, the
expression of roughly 25,000 murine genes in an affected tissue obtained
from different mouse strains can be profiled. In this hypothetical
example, assume that 2% of these genes will be differentially expressed
within tissues obtained from strains with a phenotypic difference. The
resulting list of 500 gene candidates could be computationally reduced
by 99% to about five genes, by identifying genes that are encoded
within a 15-cm chromosomal region that is linked to the trait. This
approach provides a reasonable starting point for analysis of complex
disease biology and should reduce the frustrations and overcome the
difficulties associated with QTL analysis in murine complex disease
models. Complex trait analysis will be greatly accelerated by the
development of other methods that can examine changes in all genes
within an organism. Consistent with this, it has recently been
demonstrated that gene expression levels can be analyzed as heritable
traits in mice, plants, and humans (32). Producing a catalog of gene
expression differences among commonly used inbred mouse strains
would accelerate analysis of identified chromosomal regions controlling
genetic traits. Although proteomic technologies are quite promising,
they currently lack the bandwidth needed for genome-wide analysis.
Hopefully, improved proteomic technologies will soon be developed,
which can be utilized for genetic analysis in the very near future. 5. The
problem with experimental mouse or rat models of human disease is not
with the models themselves, but with the way they have been
inappropriately utilized and interpreted. As one example, the
pathogenesis of human immune-mediated diseases has been studied in
many different rodent models. An organ-specific inflammatory
response is induced in rodent experimental models by sensitization and
subsequent re-exposure to an experimental antigen. There are mouse
and rat models of allergeninduced experimental asthma (33,34),
collagen-induced arthritis (35–37), and experimental allergic
encephalitis (38,39), in which antigen-triggered inflammation is induced
in the lungs, joints, and brain, respectively. The organ-specific
inflammation developing in these experimental models has
characteristics that resemble human asthma, rheumatoid arthritis, or
multiplesclerosis. The pharmaceutical industry has used these models
for preclinical testing of potential therapeutic agents. The effect of an
exogenous agent on the antigen-induced organ-specific inflammatory
process in these experimental models is characterized to assess whether
a potential therapeutic will have efficacy in a human disease. However,
utilization of available rodent experimental models for this purpose has
been fraught with problems. Atested compound can ameliorate
inflammation in these models by inhibiting the immune-mediated
response to the inciting antigen. Unfortunately, the clinical
manifestations of a human immune-mediated disease often appear
years to decades after an individual has been sensitized to an antigen.
In contrast, the rodent models are analyzed within days to 1 mo after
initial antigen exposure. Although initiated by an immune response to
antigen, the human immune-mediated diseases become clinically
apparent when the underlying pathogenic processes no longer involve
the initial response to the disease-inciting antigen. Therefore, efficacy in
human clinical cohorts is likely to be unrelated to efficacy in the
preclinical mouse models. The differences observed in the innate and
adaptive immune responses of mouse and man have recently been
reviewed (40). These differences can affect different components of the
immune response and can be the basis for differences in the observed
response to experimental interventions. Because there are 65–75 million
years of evolutionary distance between mouse and man, it should not be
a surprise that there are differences between these two species.
However, overemphasizing the catalog of differences between the
immune response of murine and man can lead to neglect of the key
point. The vast majority of the fundamental mechanisms and processes
regulating the murine and human immune responses are very similar.
Therefore, the mechanisms underlying immune-mediated phenotypic
differences of biomedical importance are quite likely to be shared by
mouse and man. Although the exact site at which the genetic change is
introduced is quite likely to differ between the two species, the
controlling pathways are likely to be similar.