My laboratory is interested in comprehensive analysis of the mammalian genome. For this, we utilize forward genetics, which is basically a phenotype-driven approach whereas the reverse genetics is a gene-driven approach. We think that in mammals there is currently no efficient method for forward genetics. We believe that the establishment of the following two systems is the key to success.

(1) Comprehensive and random insertion of mutation in mammalian genome
To achieve this, we adopted a new transposon system, Sleeping Beauty (SB), in mouse. We reported that SB jumped efficiently in mouse genome (Horie et al. PNAS 2001) and SB-mediated mutagenesis was successful (Horie et al. MCB 2003).
Since the SB transposon system has a unique feature that can introduce many different mutations in somatic tissues, it allows us to search for many gene functions in a single mouse. However, successful bi-allelic mutagenesis is required for analysis of gene functions (see below).

(2) Introduction of bi-allelic mutagenesis by conditionally regulated Blm gene
Somatic cells from patients with Bloom (Blm) syndrome show an increased rate of homologous recombination and therefore, result in generation of bi-allelic mutation from mono-allelic mutation. We used a tetracycline-regulated Blm allele to introduce bi-allelic mutations in ES cells (Yusa et al Nature 2004). Phenotype-based genetic is now possible and raises possibilities for identifying gene functions in ES cells. Obviously we would like to apply this system in mice.