Many important diseases such as atherosclerosis, obesity and susceptibility to infection are genetically complex. These complexities arise from multigenic control, genetic heterogeneity, variable expression, epistasis, low penetrance, modest sample sizes and difficulties in performing multiple clinical assays at different stages of development and disease progression. These complexities confound many studies to investigate the basis for inherited disease predisposition in humans. Animal models are valuable experimental systems because genetically defined inbred strains alleviate many of these problems. Although considerable progress is being made for simple genetic traits, the more common and often more important multigenic disease models remain difficult to study because essential genetic resources are not available. In this application, we propose development of two new and powerful genetic resources that are crucial for multigenic disease analysis. These resources include a panel of Recombinant Congenic Strains that are valuable for isolating and characterizing individual disease susceptibility allels. With appropriate crosses, these strains can also be combined for studying interactions between disease susceptibility and resistance alleles. The other resource we propose is a panel of Consomic Strains where chromosomes from one strain are individually transferred to another strain through back crosses and selection. By characterizing mice with single chromosome difference on a uniform genetic background, it should be possible to identify genes with subtle effects and to characterize gene interactions. Crosses with these strains can also be used for finding disease genes through the candidate gene and positional cloning paradigms. The inbred strains selected as progenitors for these two panels are A/J and C57BL/6J. Previous studies demonstrate many differences in disease susceptibility between these strains. These panels will be valuable research resources because many of these multigenic diseases are of interest to many different biomedical research communities. Work proposed in Specific Aim 1 completes inbreeding for the Recombinant Congenic and Consomic Strains. These strains will be genetically characterized by typing -2000 Simple Sequence Length Polymorphisms and embryos will be preserved as protection against accidental loss of the strains. We will use these mice in our research programs and all mice will be available to the biomedical research community. Experiments proposed in Specific Aim 2 test a novel method to accelerate inbreeding of the Consomic Strains by using genotypic selection. If this methods proves feasible, many new opportunities will be available for the efficient production of special mouse strains that are key to multigenic disease analysis.