HIGH EFFICIENCY ENU MUTAGENESIS TO ISOLATE MOUSE MODELS OF HUMAN DISEASE

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Genes on the distal portion of mouse Chr 11 are also found on human Chr 17. This extreme linkage conservation allows us to utilize the physiologic, pathologic, and molecular similarities of mouse and human in studies that exploit the experimental genetic advantages of the mouse. The primary goal of the proposed research is to obtain new mutations that reflect single gene function on the distal region of mouse Chr 11. Establishing genotype/phenotype in a specific region by mutagenesis can provide a cost effective approach to determining gene function, particularly in gene rich regions. The conserved synteny between mouse and human will provide a direct link to predications of gene function in humans. We will enhance the genetic analysis of mouse Chromosome 11 by inducing mutations with the chemical mutagen N-ethyl-N-nitrosourea. Appropriate genetic markers will be used to isolate recessive embryo and juvenile lethal and visible phenotypes in the second generation (G/2) animals. We will extend the mutational analysis by screening for multiple medically relevant recessive phenotypes that include: a) neurological, behavioral, and sensory organ defects, b) hematopoietic defects, c) autoimmune disease, d) obesity, e) infertility, and f) morphological abnormalities. Homozygous recessive embryos lethal phenotypes will be classified to a particular stage of embryonic death to understand unique aspects of mammalian development. Selected new mutations will be mapped to a higher resolution using deletion sub-intervals and complementation analysis. Some pairwise complementation tests will be performed on mutations like phenotypic classes. We will identify the genes involve din selected mutations, and correlate the molecular lesion with the biological phenotype. Mutations will be provided to the community and availability will be posted on the World Wide Web. Mutant mouse stocks will be frozen as embryos and/or sperm for archival purposes. Our work will generate many new models of human diseases, to help treat and understand diverse disorders such as behavioral maladies, birth defects, infertility, aging, and obesity that will be useful to members of the biomedical community.