This research is designed to investigate the efficient localization and ordering of major genes through linkage analysis. Although new gene mapping methods and programs have emerged, significant capabilities are still lacking and many of the statistical concepts are dated. Gene mapping can be divided into two phases: 1) initial assignment of a gene to a chromosomal region, and 2) assignment of gene order and map distance of the disease locus to all of the markers. The issues of significance and efficiency are different for these phases. In the first phase, we are testing for linkage between the disease locus and well-spaced highly polymorphic markers. Three locus evaluation of expected LOD scores and actual LOD scores are sufficient. We will investigate significance levels of the three locus analysis for testing linkage on saturated maps. For fine mapping we will compute expected LOD scores and LOD scores for gene order with multiple loci. We will also establish significance levels for comparison of orders. The preliminary LOD scores sufficient to justify a switch in strategy from localization to establishing order will be described. As the set of tools for calculating expected LOD scores and LOD scores are investigated, a knowledge-based expert system will be developed which will integrate these tools with the appropriate databases and rules. The system will be an automated tool assisting in designing the experiments, evaluating data from the experiments, and redesigning the experiment in light of the preliminary results. Thus, the large number of linkage experiments carried out in the near future can be performed efficiently.
