Forward genetics is essential to understand molecular functions in vivo. In mouse model, chemical mutagen, ENU (N-ethyl-N-nitrosourea), is widely used to induce mutations. However, since the number of introduced mutation is restricted (about 3,000 mutations / mouse) in ENU treated mice, massive screening of mutagenized mice is required to obtain desired mutant mice. We created new forward genetics model, where more mutations were accumulated in a mouse than a ENU treatment. We bred mutator mice, of which endogenous mutation rate was increased by modification of DNA polymerase δ involved in DNA replication, for a long time and generated more than 500 mutations per generation on entire genome. Thus, we could accumulate more than 6,500 mutations in the 20-generation bred mutator mice. We have established more than 20 independent inbreeding lines. So far, we obtained many mutants (dysmorphic mutants, disease-like mutants, behavioral mutants etc.) from our visible screening of the long-term bred mice. Most notable mutant was a singing (sng) mutant, which exhibited human audible vocalization after sex maturation. We identified the causative mutation in sng mutants and confirmed it by a creation of mice harboring the same mutation. Our established new forward genetics model might have a great potential to uncover molecular functions in neuroscience.