International Mammalian Genome Society

The 14th International Mouse Genome Conference (2000)

Table of Contents * Genes, Physical Mapping and Sequencing * Gene Identification * Bioinformatics * Common Resources * RIKEN Session * Functional Genomics * Complex Traits * Mutagenesis * Developmental Genetics and Differentiation * Verne Chapman Memorial Lecture I and II

D4. Large-Scale Gene Function Discovery in the Post-Genome Era

Brian Zambrowicz, Senior Vice President-Genomics, Lexicon Genetics Incorporated

The dramatic increase in the discovery of human genes has far outpaced the rate at which current technologies enable the discovery of gene function. This gene function gap has significant implications for the development of new therapeutics and diagnostics from the human genome. We have developed a systematic functional genomics methodology to discover the physiologic functions of genes in mammals on a large-scale.

Our combined methodologies of high-throughput gene trapping and rapid gene targeting have broad applicability for gene function discovery. The ability to create mutations in mouse embryonic stem (ES) cells on a large-scale provides a powerful approach for rapidly determining gene function in a mammalian system. Lexicon's gene trap technology allows for the automated production of sequence tags from the trapped genes with rapid bioinformatics analysis. We have used these techniques to create OmniBank^â that now contains over 82,000 ES cell clones and represents more than one-third of genes in the mammalian genome catalogued using bioinformatics in a relational database (www.lexgen.com).

We have implemented systems and infrastructure for the generation and analysis of mutant mice at an unprecedented rate of roughly twenty mutant lines per week. Such a capacity raises the challenge of obtaining meaningful phenotypic information from mutant lines at an equivalent pace. Fortunately, increasingly widespread recognition of the importance of mouse genetics as a tool in functional genomics has led to the miniaturization of clinical technologies such as CAT scanning, ECG, CBC, MRI and DEXA. Effective application of these technologies now permits the accumulation of physiological data on numbers of mutants, which would have been inconceivable as recently as two years ago. The rapid acquisition of meaningful physiological, structural and behavioral information in mutant mice promises to revolutionize mammalian functional genomics and drug target validation as we enter the post-genome era.