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.