International Mammalian Genome Society

The 14th International Mouse Genome Conference (2000)

H2. Mouse ENU Mutagenesis: Defining Gene Function and Modeling Human Disease

Monica J. Justice, Andrew Salinger, John S. Weber, Craig Chinault, Jim Lupski, Jan Klysik, and Allan Bradley*
Department of Molecular and Human Genetics, and
*Howard Hughes Medical Institute, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030.

The post-sequencing challenge is to define the function of genes, and large-scale high-throughput mouse mutagenesis is one of the best avenues for determining mammalian gene function. A powerful approach for mutagenesis combines gene-based targeting in embryonic stem cells with phenotype-driven ethylnitrosourea (ENU) mutagenesis. The ability to engineer whole chromosome regions using Cre/loxP technologies allows for the creation of genetic reagents such as deletions and balancer chromosomes to isolate, map and manage the large number of mutations that can be obtained from ENU mutagenesis. With a Cre/loxP gene-based approach, the endpoints of the deletions and inversions are known, minimizing the amount of effort required to characterize chromosomal rearrangements. Chromosome engineering allows the new rearrangements to be marked with a K14-agouti transgene that confers a dominant yellow coat color, providing a tool for simple mapping, stock maintenance, and genetic screens.

A balancer chromosome is being used in a three generation pedigree mating scheme to isolate recessive lethal, detrimental, and clinical disease mutations on mouse Chromosome 11, which shows extensive linkage conservation with human Chromosome 17. A number of ENU-induced mutations have been isolated, demonstrating the vigor of our approach. These mutations include recessive mutations on mouse Chr 11, as expected, but also many recessive mutations segregating genome-wide. The mutations cause many different phenotypes relevant to human disease: early embryonic and postpartum death, as well as skeletal, hematopoietic, neurological, urogenital, skin/coat and metabolic defects. New mutants, physical maps, and engineered chromosome rearrangements are described at As new mouse mutations are generated, the comparative sequence information will allow predictions of gene function in the human. Many of these new mutations will be powerful models of human diseases because mouse and human biological systems are similar. The accumulation of new mutations will alter views of mammalian gene function and developmental pathways.

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