Sleeping Beauty for mouse genetic research

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DESCRIPTION (provided by applicant): The Sleeping Beauty (SB) transposable element will be used for chromosome engineering, regional mutagenesis, and cancer genetic studies in the mouse. First, we wilt use phage C31 integrase, SB, and CRE-LoxP for chromosomal engineering in the mouse. We will create chromosomal deficiencies and inversions that will be useful for genetic screens, cloning of mutations, and strain maintenance. The generation of deficiencies that remove tumor suppressors will also be useful for modeling human tumors. Second, SB will be used for local mutagenesis. Specific regions of mouse chromosomes homologous to human disease regions will be targeted for SB-mediated mutagenesis using LoxP-containing gene traps pioneered by the Skames laboratory. Regional mutagenesis will facilitate identification of disease genes and create mouse models of human disease. Third, SB will be used to identify genes that cooperate with loss of the tumor suppressor p 19Arf (Aft) in cancer initiation and progression. This will be accomplished by mobilizing mutagenic transposons in Arf -/- mice. Arf-/- mice with novel transposon insertions that develop tumors at an earlier age than Arf-/- mice will be identified. The location of SB insertions in the tumors will be determined by PCR, and the affected gene identified. Together, these projects wilt explore the use of SB as a tool for mouse genetic research as a means for chromosome engineering, germline mutagenesis, and somatic mutagenesis.