International Mammalian Genome Society

The 14th International Mouse Genome Conference (2000)

H9. Regional Mutagenesis and Broad-based Phenotype Screening by The Tennessee Mouse Genome Consortium.

Dabney Johnson, Darla Miller, and members of the TMGC

The Tennessee Mouse Genome Consortium (TMGC) is a formal collaboration among seven institutions across the state of Tennessee to employ their academic and clinical expertise for the detection of newly induced recessive mutant phenotypes in mice. Current member institutions are Oak Ridge National Laboratory (ORNL), the University of Tennessee (UT), Vanderbilt University, the University of Memphis, East Tennessee State University, St. Jude Children's Hospital, and Meharry Medical College. Pilot programs to launch the collaboration and to generate preliminary data for funding applications were sponsored through cost-sharing by the member institutions, and by the contribution by the Department of Energy of mutagenized mice produced at ORNL.

The ORNL strategy of large-scale, phenotype-driven regional mutagenesis, primarily by the use of N-ethyl-N-nitrosourea (ENU), leads to the recovery of phenotypically significant recessive mutations that map to specific chromosomal regions. The current focus is on regions of mouse chromosomes 7, 10, 15, and X, representing about 10% of the mouse genome, and on developing genetic reagents to enable this strategy genome-wide. This strategy is designed to generate from each pedigree multiple, visibly marked test-class mice all homozygous or hemizygous for the identical mutagenized chromosome, permitting distribution of animals for multi-site screening, shelving for aging/rescreening for later-onset phenotypes, and a statistically useful sample size from each pedigree tested for innately variable phenotypes.

Concurrent ENU-mutagenesis at UT is focused on recessive phenotypes recovered on a mouse chromosome 19 isolated in a consomic strain, with these potentially mutant pedigrees also distributed for multi-site TMGC screening.

Pilot programs have supported primary screening of nearly 700 pedigrees from experiments performed at ORNL targeting the pink-eyed dilution region of mouse chromosome 7 for visible and lethal phenotypes as well as more subtle, behavioral, biochemical, and morphological abnormalities. For primary screens for which variable scores are expected (e.g., behavior tests), four test-class mice per pedigree are scored, and pedigrees from which all four mice fall below the tenth percentile or above the ninetieth percentile relative to the entire population tested are flagged as "variant". In this pilot, we have confirmed as heritable five embryonic or juvenile lethals, five subtle behavioral abnormalities, and have additional potential variants in various stages of heritability testing.

The TMGC, governed by Administrative, Scientific, and Veterinary Steering Committees, an internal Executive Committee, and an External Advisory Board, is committed to the immediate sharing of all confirmed mutant stocks, and will supply those mice by rederivation in specific-pathogen free (SPF) conditions.

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