PI: Jiří Forejt Genetically Defined Mice Models as a Tool for Studying Human Diseases
While the analysis in human genomics is currently focusing on the genome-wide association studies (GWAS), the mouse model offers a complementary approach using genetic fractionation of polymorphisms on the model of the chromosome substitution strains (= consomic strains) and the recombinant inbred (RI) strains (see the current international project 1000 RI strains, Collaborative Cross). So far only 4 complete panels of the chromosome substitution strains exist in the world. Two of them were prepared in the USA, one in our laboratory and one in Japan.
We were first to use a powerful genetic polymorphism that occurred during evolution of two mouse sub-species; Mus m. musculus and Mus m. domesticus to create a panel of consomic strains. Mice from our consomic strains have been partly phenotyped in the PHENOME program in The Jackson Laboratory, Bar Harbor, USA.
These mice serve as a universal tool for studying wide range of complex human diseases as mentioned above. The consomic strains will find a special use in studying the modifier genes and for studying the genes controlling production of functional sperm.
Analysis of two mouse models of genetically controlled male infertility. To understand the principles of the epigenetic, parent-of-origin effects on meiosis of male-sterile chromosomal translocation carriers we are studying chromation modification in primary spermatocytes of the reciprocal +/T43H male hybrids which differ in the extent of meiotic pertubations. We will analyze the transcription profile changes associated with this type of transgenerational inheritance and we will study differential epigenetic marks established on a chromosomal domain of T43H translocation such as DNA methylation and histone modifications within germ cell lineage development.
The other model gains information of the role of individual genes in infertility by following the cellular, subcellular and molecular traits associated with male infertility in mouse sub-species Mus m. musculus and Mus m. domesticus hybrids the new knowledģe obtained from the mouse infertility model will be applied on data from human male infertility studies. As an example, our recent discovery of Prdm9 gene as mouse hybrid sterility prompted subsequent follow up of this gene in patiens of human infertility clinics.