FUNCTIONAL GENOMICS IN THE MOUSE - PHENOTYPE-BASED MUTAGENESIS SCREENS

Significant progress has been made in sequencing the genomes of severa l model organisms, and efforts are now underway to complete the sequen cing of the human genome. In parallel with this effort, new approaches are being developed for the elucidation of the functional content of the human genome, The mouse will have an important role in this phase of the genome project as a model system. In this review we discuss and compare classical genetic approaches to gene function-phenotype-based mutagenesis screens aimed at the establishment of a large collection of single gene mutations affecting a wide range of phenotypic traits i n the mouse. Whereas large scale genome-wide screens that are directed at the identification of all loci contributing to a specific phenotyp e may be impractical, region-specific saturation screens that provide mutations within a delimited chromosomal region are a feasible alterna tive. Region-specific screens in the mouse call be performed in only t wo generations by combining high-efficiency chemical mutagenesis with deletion complexes generated using embryonic stem (ES) cells. The abil ity to create and analyze deletion complexes rapidly, as well as to ma p novel chemically-induced mutations within these complexes, will faci litate systematic functional analysis of the mouse genome and correspo nding gene sequences in humans. Furthermore, as the extent of the mous e genome sequencing effort is still uncertain, we underscore a necessi ty to direct sequencing efforts to those chromosomal regions that are targets for extensive mutagenesis screens.