The International Complex Trait Consortium

Dissection of the complexity of polygenic body weight regulation in selected mouse lines

Gudrun A. Brockmann, Ulla Renne, Marianna Bevova

Research Institute for the Biology of Farm Animals, Wilhelm-Stahl-Allee 2, 18196 Dummerstorf

ABSTRACT
 
The high body weight-selected mouse line DU6i is a polygenic model for growth research. DU6i is an inbred derivate of DU6 which has been selected for high body weight at 6 weeks. DU6 descends from an original crosses of four base (NMRI orig., Han:NMRI, CFW, CF1) and four inbred (CBA/Bln, AB/Bln, C57BL/Bln, XVII/Bln) populations in the Research Institute for the Biology of Farm Animals. Genes influencing body weight and composition and serum concentrations of leptin, insulin, and IGF-I in non-fasting animals were mapped in an intercross of the extreme high growth mouse line DU6i and the inbred line DBA/2. Significant loci with major effects (F>7.07) for body weight, obesity and muscle weight were found on chromosomes 1, 4, 5, 7, 11, 12, 13, and 17, for leptin on chromosome 14, for insulin on chromosome 4, and for IGF-I on chromosome 10 at the Igf1 gene locus itself and on chromosome 18. Significant interaction between different QTL positions was observed (P<0.01). Evidence was found that loci having small direct effect on growth or obesity contribute to the obese phenotype by gene*gene interaction. The effects of QTLs, epistasis, and pleiotropy account for 64 % and 63 % of the phenotypic variance of body weight, and fat accumulation, and for over 32 % of muscle weight and serum concentrations of leptin, and IGF-I in the F2 population of DU6i x DBA/2 mice. For the targeted study of isolated QTLs and gene-gene-interactions, and for the final discovery of underlying genes, we construct chromosome substitution strains (CSS) for Du6i mice. The novel strains will allow comprehensive phenotypic screens, which will likely provide distinct sub-phenotypes which better combine phenotypes and genotypes.

References

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Schüler, L (1985) Mouse strain Fzt:Du and its use as model in animal breeding research. Arch. Tierzucht 28: 357-363.

Brockmann, G.A.; Haley, C.S.; Renne, U.; Knott, S.A.; Schwerin, M. (1998): QTLs effecting body weight and fatness from a mouse line selected for extreme high growth. Genetics 150: 369-381

Brockmann GA.; Kratzsch, J., Haley, C.S., Renne, U., Schwerin, M., Karle, S. (2000): Single QTL effects, epistasis, and pleiotropy account for two thirds of the phenotypic F2 variance of growth and obesity in DU6i x DBA/2 mice. Genome Res. 10: 1941-1957

Brockmann, G.A.; Haley, C.S.; Wolf, E.; Karle, S.; Kratzsch, J.; Renne, U.; Schwerin, M.; Hoeflich, A. (2001): Genome-wide search for loci controlling serum IGF-binding protein levels of mice. FASEB J. 15: 978-987

[This work was supported by the German Research Foundation and the H. Wilhelm-Schaumann Stiftung.]