GENETIC AND MOLECULAR ANALYSES OF MUTATIONS

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DESCRIPTION: The p locus is extraordinary in many ways, including the variety of mutations with diverse phenotypic effects, instability of a particular allele with frequent reversions to wild-type, nearly complete genetic and physical maps of both the mouse and the corresponding region of the human genome, biologically interesting and medically important diseases that map to this region of the human genome. The key to dissecting this region was the applicant's discovery that the pun mutation was a genomic duplication that frequently reverted to wild- type. This discovery soon led to cloning the p gene, to complementation tests among the many alleles at this locus, the assignment of various phenotypic effects (growth retardation, male sterility, female semi- sterility, cleft palate, neurological disorders, behavioral abnormalities, and prenatal lethality) to specific deleted portions of the locus, the development of genetic and physical maps for locating other candidate genes for particular diseases that map to this locus, and the use of these reagents to evaluate diseases (Prader-Willi, Angelman, tyrosinase positive oculocutaneous albinism) that map to the corresponding region of the human genome. The applicant made remarkable progress during the previous funding period. The focus of this renewal application is to understand the molecular basis for the non- pigmentation phenotypes of p deletions and to identify, clone and characterize the responsible genes. Specific Aim 1 is to complete the genetic and physical map of the p locus. The maps are largely complete and by filling in the gaps Brilliant will be able to more quickly identify and evaluate candidate genes. These maps and reagents will also facilitate analysis of diseases genes located in the corresponding region of the human genome. Specific Aim 2 is to evaluate a candidate gene for disorders in growth, neurological function, behavior and fertility associated with independent mutations at the p locus. Brilliant and his collaborators used complementation tests with three p alleles to argue that a single gene in this region affects growth, behavior, fertility and neurological function. A candidate gene from the critical region has been cloned, characterized and partially sequenced. Specific Aim 3 is to identify the molecular basis for cleft palate and the abnormal neurological function associated with the pcp mutation.