The International Complex Trait Consortium

Dominant screening using HIB (Heavy Ion Beam) mutagenesis Combined with large backcross studies

Hiroki Nagase1, Makoto Kimura1, Jun Igarashi1, Atsushi Yoshiki2, Chikako Yoshida-Noro2, Jian-Hua Mao3, Allan Balmain3,4

1Roswell Park Cancer Institute, Department of Cancer Genetics, Buffalo NY 14263-0001 USA
2Experimental Animal Division, BioResource Center, RIKEN Tsukuba Institute, Japan
3UCSF Comprehensive Cancer Center and Cancer Research Institute, University of California, San Francisco, CA 94115 USA
4Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94143 USA

ABSTRACT
 
Studies of mouse models of human cancer have demonstrated the existence of germline genetic modifiers that influence cancer susceptibility. Although many tumor modifier loci have been localized to regions of 10 to 30 cM, fine mapping and identification of these low-penetrance genes has proven to be time-consuming and expensive. Here, we discuss the possibility of a novel approach involving a combination of linkage analysis and dominant mutant screening to refine a locus conferring skin papilloma susceptibility to at least a 2-Mb region of mouse chromosome 9. We employed Heavy Ion Beam (HIB); Ne Ion Beam, as an alternative mutagen instead of chemical mutagens such as ENU. HIB irradiation can induce small deletions in the genome and modified inheritable effect in the next generation. Thus, a large dominant screening has been performed to more than 300 G1 animals from irradiated Mus spretus G0 males and FVB/N females. Although F1 hybrids of resistant Mus spretus and susceptible FVB/N confers resistance to skin cancer development, we found a G1 animal with many skin papillomas after the two-stage chemical carcinogen protocol had at least a 2Mb deletion at SKTS6 (Skin tumor susceptibility 6) locus, which was mapped by a large backcross using the same strains.

Our approach takes advantage of the possibilities of combining linkage and mutagenesis genetic strategies for identification of genes relevant to mouse cancer susceptibility. Subsequently, we hope we can confirm the cancer susceptibility gene in humans.

References

Epistatic interactions between skin tumor modifier loci in interspecific (spretus/musculus) backcross mice. Nagase, H., Mao, J.H., de Koning, J.P., Minami, T., and Balmain A. Cancer Research 61: 1305-1308, 2001.

Dose dependent effects of heavy ion beams irradiation on the testes in mice. Yoshiki, A. Kogiso, A., Hiraiwa, N., Ike, F., Nagase, H., Yoshida-Noro, C., Fukunishi, N., and Kusakabe, M. RIKEN Accel. Prog. Rep. 34: 173, 2001.

Mouse Mutagenesis by Heavy Ion Beam for the profiling of Morphogenetic Genes. Yoshida-Noro, C., Yoshiki, A., Kusakabe, M., Matsuyama, T., and Nagase, H. RIKEN Accel. Prog. Rep. 34: 174, 2001.

[This work supported by the ROSWELL PARK ALLIANCE FUNDS and Grant in Aid for Scientific Research, Special Research Fields (A), Ministry of Education and technology, Japan]