International Mammalian Genome Society

The 15th International Mouse Genome Conference (2001)


LARGE-SCALE ISOLATION AND RAPID MAPPING OF RECESSIVE MUTATIONS USING A MOUSE BALANCER CHROMOSOME

Monica Justice
Department of Molecular and Human Genetics
Baylor College of Medicine
One Baylor Plaza
Houston TX 77030, USA

Co-Authors: 1)Salinger A, 1)Clark A, 1)Hentges K, 1)Box N, 1)Holdsworth A, 1)Maffucci J, 1)Ross M, 1)Liu B, 2)Behringer B, 3)Bradley, A 1)Justice M
Institutions: 1) Baylor College of Medicine, 2)The University of Texas M.D. Anderson Cancer Center, Houston, TX 2) The Sanger Centre, Hinxton, UK

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 chromosome engineering in embryonic stem cells with phenotype-driven ethylnitrosourea (ENU) mutagenesis. Chromosome engineering allows molecularly defined inversions to be marked with a K14-agouti transgene that confers a dominant yellow coat color, providing a tool called a balancer chromosome for simple mapping, stock maintenance, and genetic screens.

A Cre-loxP engineered balancer chromosome is being used in a three generation pedigree mating scheme to isolate recessive mutations on mouse Chromosome 11, which shows extensive linkage conservation with human Chromosome 17. The new ENU-induced mutations include recessive mutations mapping to mouse Chr 11, as well as those segregating genome-wide, demonstrating the dual benefits of this genetic strategy for large-scale mutation isolation. The phenotypes are relevant to human disease, causing early embryonic and postpartum death, infertility, as well as skeletal, hematopoietic, neurological, urogenital, skin/coat and metabolic defects. Surprisingly, nearly 2/3 of the new mutations mapping to mouse Chr 11 cause early death or infertility, phenotypes that would be difficult to manage without the use of a balancer. In future studies, we will generate balancer chromosomes that will cover 25% of the mouse genome. 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. The accumulation of new mutations will alter views of mammalian gene function and developmental pathways.


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