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In the post-genome era, the mouse will have a major role as a model system for functional genome analysis. This requires a large number of mutants similar to the collections available from other model organisms such as Drosophila melanogaster and Caenorhabditis elegans . Here we report on a systematic, genome-wide, mutagenesis screen in mice. As part of the German Human Genome Project, we have undertaken a large-scale ENU-mutagenesis screen for dominant mutations and a limited screen for recessive mutations 1 . In screening over 14,000 mice for a large number of clinically relevant parameters, we recovered 182 mouse mutants for a variety of phenotypes. In addition, 247 variant mouse mutants are currently in genetic confirmation testing and will result in additional new mutant lines. This mutagenesis screen, along with the screen described in the accompanying paper 2 , leads to a significant increase in the number of mouse models 3 available to the scientific community. Our mutant lines are freely accessible to non-commercial users (for information, see http://www.gsf.de/ieg/groups/enu-mouse.html ).

The Munich ENU Mouse Mutagenesis Screen is a large-scale mutant production, phenotyping, and mapping project. It encompasses two animal breeding facilities and a number of screening groups located in the general area of Munich. A central database is required to manage and process the immense amount of data generated by the mutagenesis project. This database, which we named MouseNet©, runs on a Sybase platform and will finally store and process all data from the entire project. In addition, the system comprises a portfolio of functions needed to support the workflow management of the core facility and the screening groups. MouseNet© will make all of the data available to the participating screening groups, and later to the international scientific community. MouseNet© will consist of three major software components:• Animal Management System (AMS)• Sample Tracking System (STS)• Result Documentation System (RDS)MouseNet© provides the following major advantages:• being accessible from different client platforms via the Internet• being a full-featured multi-user system (including access restriction and data locking mechanisms)• relying on a professional RDBMS (relational database management system) which runs on a UNIX server platform• supplying workflow functions and a variety of plausibility checks.

The Munich ENU Mouse Mutagenesis Project within the German Human Genome Project is a phenotype-driven approach to produce, identify, and characterize new mouse mutants (Hrabe de Angelis and Balling 1998). The focus of the clinical-chemical screen is on laboratory diagnostic procedures (mainly bloodbased) suitable to detect hematological changes, defects of various organ systems, and changes in metabolic pathways and electrolyte homeostasis. The methods used are appropriate routine procedures, allowing the screening of large numbers of mice for a broad spectrum of clinical-chemical and hematological parameters. Since most inherited metabolic disorders in humans are known to lead directly or indirectly via altered organ function to changes in the parameters investigated (Fernandes et al. 1995; Saudubray and Charpentier 1995), this screen provides a comprehensive investigation of clinical phenotypes with known counterparts in humans.

Recent in vivo and in vitro data of patients analyzed for genetic susceptibility to radiation during cancer therapy have shown structural changes in the chromosomes to be prevalent both in the patients being treated and in their immediate family members. As structural changes in chromosomes frequently lead to activation of proto-oncogenes and elimination of tumor-suppressor genes, they represent important mechanisms for the initiation of DNA repair processes and tumorigenesis. With the exception of rare genetic syndromes such as AT (Ataxia telangiectasia) or NBS (Nijmegen Breakage Syndrome), the background for the inheritance of genetic susceptibility to radiation is unknown.Recently, a large-scale genetic screen of mouse mutants has been established within the German Human Genome Project (Hrabè de Angelis and Balling 1998). The goal of this ENU (ENU: ethylnitrosourea) mutagenesis screen is the generation of mutant mice that will serve as animal models for human diseases and genetic susceptibility.In order to fully utilize the potential of a genetic screen of this magnitude, in which exploration for genes responsible for genomic instability and radiation sensitivity is to occur, it is necessary to establish a simple assay system that is amenable to automation. Hence, we are using the single-cell gel electrophoresis (comet assay) to detect mouse mutants that display a genetic susceptibility to ionizing radiation. We have established the analysis parameters in the comet assay which are currently used to detect radiation-sensitive mouse mutants and to control the variance within the mouse population in the ENU screen. The assay can be used to isolate genes that are responsible for DNA repair and radiation sensitivity in mouse and human.

The Munich ENU Mouse Mutagenesis Screen is a large-scale mutant production, phenotyping, and mapping project. It encompasses two animal breeding facilities and a number of screening groups located in the general area of Munich. A central database is required to manage and process the immense amount of data generated by the mutagenesis project. This database, which we named MouseNet copyright , runs on a Sybase platform and will finally store and process all data from the entire project. In addition, the system comprises a portfolio of functions needed to support the workflow management of the core facility and the screening groups. MouseNet copyright will make all of the data available to the participating screening groups, and later to the international scientific community. MouseNet copyright will consist of three major software components: Animal Management System (AMS); Sample Tracking System (STS); Result Documentation System (RDS) MouseNet copyright provides the following major advantages: being accessible from different client platforms via the Internet; being a full-featured multi-user system (including access restriction and data locking mechanisms); relying on a professional RDBMS (relational database management system) which runs on a UNIX server platform; and supplying workflow functions and a variety of plausibility checks.

Within the next few years the complete sequence of the human genome will be available (Schuler et al. 1996), and the postgenome era will start with the systematic analysis of gene function and its role in human pathogenesis and disease. Characterization of spontaneous and induced mutants, the analysis of transgenic and gene-targeted phenotypes in animals, i.e., fruitfly, zebrafish, or rodents, are common tools to obtain insight into the biological function of genes. With respect to the genetics and pathogenesis of human diseases, animal models are essential for further investigations; and in particular, the mouse has had a major role as a model system owing to the similarity of its genome, developmental and biochemical pathways, and physiology to humans. Two different strategies can be attempted for the systematic production of mutant phenotypes in the mouse: the gene-driven approach is based on the mouse embryonic stem cell technology, in which mouse mutants can be generated for any targeted mutation engineered through homologous recombination.