International Mammalian Genome Society


The 13th International Mouse Genome Conference
October 31-November 3, 1999

Table of Contents * Structure * Bioinformatics * Sequence * Mapping * New Tools * Gene Discovery * Developmental * Mutagenesis * Functional Genomics

H8 The Mouse Genome Project at Baylor College of Medicine: Combining Gene-Based and Phenotype-Based Approaches for Functional Genomics

Monica J. Justice, Binhai Zheng, John S. Weber, Andrew Salinger, Alea A. Mills, Jan Klysig, Craig Chinault, 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 rapid accumulation of sequence information is having a major impact on the direction of biomedical research. 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 ENU mutagenesis. The ability to engineer whole chromosome regions using Cre/loxP technologies allows the creation of genetic reagents such as deletions and balancer chromosomes for isolating and managing the large number of mutations that can be obtained from ENU mutagenesis1. 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 tags the new rearrangements with a dominant yellow coat color marker, K14-agouti, providing a tool for simple mapping, stock maintenance, and genetic screens2.

Our goal is to isolate recessive lethal, detrimental, and clinical disease mutations on mouse Chromosome 11, which shows extensive linkage conservation with human Chromosome 17. Our preliminary work has already generated a number of ENU-induced mutations, demonstrating the vigor of our approach. New mutants, physical maps, and engineered chromosome rearrangements are described at www.mouse-genome.bcm.tmc.edu. 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. Our view of gene function and developmental pathways in mammals will be dramatically and permanently changed by these experiments.

1Zheng et al. 1999. Engineering a mouse balancer chromosome. Nature Genetics, in press.

2Zheng et al. 1999. A system for rapid generation of coat color-tagged knockouts and defined chromosomal rearrangements in mice. Nucleic Acids Research 27, 2354-2360.

 


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