International Mammalian Genome Society

The 16th International Mouse Genome Conference (2002)


I Nishijima
Department of Molecular and Human Genetics, Baylor College of Medicine

2) Mills A, 1) Qi Y, 1) Mills M, 1) Banik P, and 1)3) Bradley A
1) Baylor College of Medicine, 2) Cold Spring Harbor Laboratory, 3) The Wellcome Trust Sanger Institute

Loss of heterozygosity (LOH) in the region of human 1p32-36 has been observed in a wide variety of cancers including leukemia, breast, lung, intestinal, liver and neuroblastoma. In particular, a deletion of 1p32-36 is frequently observed in the blast crisis phase of chronic myelocytic leukemia.  This suggests that there are one or more tumor suppressor genes that suppress progression to the malignancy in the region of 1p32-36.  Using the Cre/loxP chromosome engineering strategy, we have generated a series of ES cell lines and mice with large deletions and inversions on the distal region of mouse chromosome 4.  In sum, this deletion series encompass a 40cM region of mouse chromosome 4, and the size of each deletion is 1-5cM.  The deletion events were confirmed by fluorescence in situ hybridization.  Deletion strains exhibiting an increased leukemia susceptibility will be analyzed in a combination with mutated oncogenes and tumor suppressor genes such as Ras, p53 and bcr-abl, which is accelerate tumorigenesis.  In addition to large deletions, two mouse strains that carry large inversions on the distal region of mouse chromosome 4 were generated.  The inversion intervals are 16 and 22 cM in size; in sum they cover approximately half of chromosome 4. Since recombination between the wild type and inversion chromosomes does not occur within these inversion intervals, mutant alleles of genes mapping to this region can be identified and maintained.  Therefore, these inversion chromosomes work as balancer chromosomes.  These inversions have the additional advantage of being tagged with genes encoding the visible coat color markers tyrosinase and agouti, and therefore the dosage of each inversion chromosome (+/+, Inv/+, Inv/Inv) can be visually recognized.  These deletion and inversion strains will be extremely useful for the identification and maintenance of recessive mutants such as tumor suppressor genes on chromosome 4, and for mutagenesis screens that focus on functional analysis of human chromosome 1p32-36.

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