PROJECT SUMMARY (See instructions): Core C (Annotation) will fie together all of the Cores in this U19 program, as well as Projects 1 through 3, by annotating mutations found in sequencing Gl mutant exomes and disseminating data related to phenotypic mutations. It will coordinate the activities of the U19, and also grant the scientific community ready access to germline mutant mice that are available nowhere else in the world. The central vehicle for this process will be Mutagenetix, a website developed and tested over a period of four years by the Beutler and Goodnow laboratories, and slated for further development in the context of this program. Mutagenetix catalogues both phenotypic mutations (those known to cause phenovariance in mice, because they were detected in phenotypic screening), and incidental mutations (those that may or may not cause phenotype, because they were found through whole genome or whole exome sequencing). The latter category of mutations is growing rapidly, and more than 200,000 incidental mutations will be produced in the course of the five year project we propose. Each incidental mutation will be analyzed using an automated informatic process to assess the likelihood of an effect on protein structure, and every affected gene will also be functionally annotated by knowledgeable individuals Each incidental mutation will be made available in the form of germline mutant mice, derived from sperm that have been cryopreserved and archived for quick retrieval. Guided by Project 3 and Cores B and D, the Core A (Genetics) will make mice available for advanced, hypothesis-driven phenotypic analysis of the effects of mutations induced by ENU in specific genes. Multiple alleles of a single gene may be studied, along with allelic variants of multiple genes predicted to participate in individual biological functions. The Annotation Core will therefore support two basic enterprises. Unbiased forward genetics (Projects 1 and 2) will yield data that will be disseminated via Mutagenetix. And hypothesis-driven reverse genetics (Project 3) will permit the identification of even subtle effects of mutations that would not easily be detected in forward screening. The Annotation Core may be seen as the organizational heart of the U19.

RELEVANCE (See instructions): Core C (Annotation) will provide the essential organizational basis for distribution and use of mutant mouse models, both by members of this U19 program, and by the scientific community at large. These models can be applied to the study of many diseases, relevant to immunology (the main subject of the U19 program), and to other biomedical disciplines. Virtually every gene in the mouse genome will be affected by mutations we produce, and in Core C, they will be displayed for retrieval, and their effects described.