Beyond the Identification of Transcribed Sequences:
Functional, Evolutionary and Expression Analysis
12th International Workshop
October 25-28, 2002
Washington, DC


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Functional Analysis of the Mammalian Genome by Large Scale Gene Trap Mutagenesis

Harald von Melchner
Laboratory for Molecular Hematology, University of, Frankfurt am Main, 60590 GERMANY

Gene trap mutagenesis in mouse embryonic stem (ES) cells is a complementary approach to the functional annotation of the mouse genome. In concert with chemical (ENU) mutagenesis, the approach enables the analysis of gene function in the context of the entire organism and thus furthers our understanding of human disease. We have established a Research Consortium (German Gene trap Consortium, GGTC) to carry out large scale gene trap mutagenesis in ES cells. Its goal is to contribute to the saturation mutagenesis of the mouse genome and to generate a mouse model for each gene in cooperation with the International Mouse Mutant Consortium (IMMC). Towards this goal, the GGTC has generated 16,000 mutant ES cell lines and has identified the gene trap integration sites in 7332 clones. Of the generated gene trap sequence tags (GTSTs), 4,530 informative sequences were obtained of which 2,463 corresponded to known genes, 794 to ESTs and 1,273 to putative novel genes. Of all integrations into previously characterized genes, 66 occurred in genes involved in human disease. Furthermore, we have generated over 70 germ line chimeras and could show that 62% of resulting homozygous mutants exhibit an obvious phenotype. As for most available mouse mutant strains the significance for human disease is uncertain because germline mutations can reveal only the earliest, non-redundant role of a gene, we have also developed a gene trap approach to induce conditional mutations in ES cells. Finally, data obtained from individual clones, such as GTSTs, expression patterns and phenotypes, are deposited in the GGTC's database which is publicly accessible via http://genetrap.de. Corresponding cell lines, stored frozen at the GSF in Munich, are available freely upon request.



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