Graft-versus-host disease (GVHD) is the major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation. From a genetic perspective, GVHD is a complex phenotypic trait. Susceptibility for GVHD results from interacting polymorphisms of genes encoding histocompatibility antigens and regulatory molecules that augment or dampen allogeneic immune responses. A detailed and integrative understanding of the genetic background underlying GVHD remains lacking, however, and novel molecular targets for effective GVHD therapy are needed. We therefore propose to identify genes encoded by a locus on mouse chromosome 16, named the Gvh locus, which renders major susceptibility to lethal GVHD (LOD = 9.1). We discovered the gene locus by linkage analysis of an experimental cross in a mouse bone marrow transplant model. In this model, B10.BR mice are resistant whereas BALB.K mice are highly susceptible to severe and lethal GVHD after transplantation. We have validated linkage of the Gvh locus through construction of a B10.BRChr16 BALB.K chromosome substitution strain (CSS). Introgressing deleterious alleles from BALB.K chromosome 16 onto the resistant B10.BR background in the CSS resulted in near complete reexpression of GVHD susceptibility. To identify Gvh genes, we propose the following Specific Aims: (1) fine map the Gvh locus using interval specific congenic mouse lines and (2) in silico haplotype mapping; (3) perform functional, expression and bioinformatic analyses to prioritize candidate Gvh genes; and (4) identify causative Gvh genes by positional cloning. Successful gene discovery by this proposal will yield new insight into genetic control mechanisms regulating GVHD and potentially reveal novel approaches for effective GVHD therapy.