International Mammalian Genome Society

logo18th International Mouse Genome Conference

17-22 October 2004, Seattle, USA


POSTER 40 - PREDISPOSITION TO MOUSE THYMIC LYMPHOMAS DEPENDS ON COMMON VARIANT ALLELES OF MTF-1 (METAL RESPONSIVE TRANSCRIPTION FACTOR-1)

Kominami R1, Tamura Y1, Maruyama M1, Mishima Y1, Schaffner W2

1 Niigata University, Graduate School of Medical and Dental Sciences, Niigata, Japan, 2 Institute for Molecular Biology, University of Zurich, Zurich, Switzerland

Genetic predisposition to cancers is significant to public health because a high proportion of cancers probably arise in a susceptible human subpopulation. One major model for polygenic predisposition is the common variant-common disease model, in which common variants that have arisen only once, early in the history of the population, underlie disease predisposition in humans and perhaps in mice. The mapping and isolation of such variants in humans are complicated by the multiplicity of unlinked loci, whereas for mouse models of cancer susceptibility experimental strategies exist for fine mapping of complex traits. Using a mouse model of g -ray induced thymic lymphomas, we performed linkage analysis and haplotype mapping that identified Mtf-1, metal responsive transcription factor-1, as a candidate lymphoma susceptibility gene. The Mtf-1 allele inherited from resistant strains exhibited higher radiation inducibility of target genes than that of susceptible strains, and products of the targets such as metallothionein are able to suppress cellular stresses generated by irradiation. Therefore, this suggests that highly inducible strains are refractory to radiation effects and hence are resistant to lymphoma development. Interestingly, the Mtf-1 polymorphism was common to different mouse subspecies, consistent with the common variant-common disease model.

Genetic predisposition to cancers is significant to public health because a high proportion of cancers probably arise in a susceptible human subpopulation. Using a mouse model of g -ray induced thymic lymphomas, we performed linkage analysis and haplotype mapping that identified Mtf-1, metal responsive transcription factor-1, as a candidate lymphoma susceptibility gene. The Mtf-1 allele inherited from resistant strains exhibited higher radiation inducibility of target genes than that of susceptible strains, and products of the targets such as metallothionein are able to suppress cellular stresses generated by irradiation. Therefore, this suggests that highly inducible strains are refractory to radiation effects and hence are resistant to lymphoma development. Interestingly, the Mtf-1 polymorphism was common to different mouse subspecies, consistent with the common variant-common disease model.

Genetic variation plays a key role in determining the range of individual susceptibility to cancers in human. A high proportion of cancers probably arise in a susceptible subpopulation that carry low-penetrance variant alleles. One major model for polygenic predisposition is the common variant-common disease model, in which common variants that have arisen only once, early in the history of the population.

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