|Function and cDNA Resources Section
DOE Human Genome Program Contractor-Grantee
103. Designing Genetic Reagents to Facilitate the Mutagenesis and Functional Analysis of the Mouse Genome
Edward J. Michaud1,2, Qing G. von Arnim1,2, Carmen M. Foster1,4, Yun You1,2, Dabney K. Johnson1,2, and Eugene M. Rinchik1,2,3
1Mammalian Genetics and Development Section, Life Sciences Division, Oak Ridge National Laboratory, P.O. Box 2009, Oak Ridge, TN 37831-8077; 2University of Tennessee - Oak Ridge National Laboratory Graduate Program in Genome Science and Technology; and 3Department of Biochemistry, Cellular and Molecular Biology, University of Tennessee, Knoxville, TN 37996-0845, and 4Department of Pathology, College of Veterinary Medicine, University of Tennessee, Knoxville, TN 37901-1071
Analysis of the molecular, cellular, and organismal consequences of induced and spontaneous mutations in mouse genes provides insight into the roles that genes play in human biological systems and disease. The complete DNA sequences of the human and mouse genomes will soon be available, and strategies are being developed to annotate the physical maps with gene-function maps. For many years, ORNL has used a phenotype-driven chromosome-region mutagenesis strategy in the mouse to map gene function in pre-selected segments of the genome. Currently, we are applying this strategy to approximately 8% of the mouse genome (see abstract by Rinchik et al.). In collaboration with the Joint Genome Institute (JGI), we are also conducting molecular, genomic, transcriptional, and DNA-sequence analyses of our mutagenized regions in order to integrate the genetic mutation maps with the transcript maps (see abstract by Johnson et al.).
This project forms the third component of the ORNL mutagenesis program; designing genetic reagents to facilitate regional-mutagenesis and functional-genomics analyses in additional portions of the genome. Our regional-mutagenesis strategy is based on having visibly marked (altered coat color, for example) chromosomal deletions or inversions in order to perform the mutagenesis and gene-function mapping in the most cost-effective, high-throughput, user-friendly, and error-free manner. However, the genetic reagents that facilitate these regional-mutagenesis screens are currently available for a limited portion of the mouse genome. We are employing embryonic stem-cell strategies to design marked chromosomal alterations in large, gene-rich regions of mouse chromosomes that are in synteny conservation with portions of the human genome being mapped and sequenced by the JGI. These reagents will facilitate additional mutagenesis screens in the mouse for the purpose of annotating human DNA sequence information with the whole-organism biological functions of genes. Our initial focus is on the proximal 23 cM of mouse Chromosome 7 (human 19q homology) and a 16 cM region of proximal mouse Chromosome 11 (human 5q homology). Efforts are also under way to complement the chromosome-region mutagenesis program by developing an integrated, systems-biological approach to analyzing complex multigenic traits in mice (see abstracts by Doktycz et al., and Snoddy et al.).
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