The central goal of this project will be to test the hypothesis that sequence variants near the heterogeneous boundaries of the highly conserved A1-B8-DR3 ancestral MHC haplotype are causative of type 1 diabetes (T1D). By identifying the boundaries in a set of chromosomes, and then comparing extensive, complete, and phased high quality sequence data from targeted boundaries between conserved and recombinant regions identified in patients and controls, we propose that variations that modulate the course of diabetes can be identified. Derivative from this work we propose to develop typing methods which can be used to screen individuals before the age of disease onset, in order to identify high risk individuals and maximize the potential for preventative therapy. This project will also represent an important application of state of the art genomics technology that will provide access to clone resources and sequence data that can be widely disseminated to an extensive scientific community with longstanding interest in the biological problem that the RFA addresses. Towards these ends, we propose to achieve the following specific aims: 1) To precisely define the boundaries of the A1-B8-DR3 haplotype in T1D case and control chromosomes, 2) To construct fosmid libraries from A1- B8-DR3 individuals equally divided over T1D cases and controls, 3) To sequence regions defined in specific aim 1 from the libraries developed in specific aim 2, with the aim of identifying sequence variants that could be relevant to disease susceptibility, 4) To validate results obtained in specific aim 3 on a larger group of cases and controls, thereby establishing a simple genetic test(s) with powerful predictive capability to identify T1D patients before onset. Should genetic variants that distinguish A1-B8-DR3 chromosomes found in T1D patients from normal controls be found, this research has the potential to lead to the development of a test(s) useful in a clinical setting for the determination of T1D risk in susceptible human populations. Further potential to provide new direction in the treatment of T1D may emerge through an understanding of the functional consequences of that variation, and its relationship to other T1D risk haplotypes. ? ? ?