International Mammalian Genome Society

17th International Mouse Genome Conference

9-12 November 2003, Braunschweig, Germany


POSTER 24 - VELOCIGENE: A HIGH-THROUGHPUT APPROACH FOR GENOME ENGINEERING, ASSIGNMENT OF GENE FUNCTION AND HIGH-RESOLUTION EXPRESSION ANALYSIS IN MICE

Adams N C
Regeneron Pharmaceuticals, Inc.

Co-Authors: Economides A N, Murphy A J, Kraus P, Gale N W, Auerbach W, Frendewey D, DeChiara T M, Valenzuela D M, Yancopoulos G D
Institutions: Regeneron Pharmaceuticals, Inc.

We have developed a high-throughput and flexible method for engineering the mouse genome. This method utilizes Bacterial Homologous Recombination allowing for very precise modification of Bacterial Artificial Chromosomes to generate targeting vectors (BACvecs). Large deletions (>100 kb), reporter genes, gene swaps as well as subtle changes such as point mutations or conditional alleles can be generated with equal ease as knock-out /knock-in and transgenic alleles. The high-throughput use of BACvecs as targeting vectors is made possible by a Quantitative PCR-based method for identifying targeted Embryonic Stem cell clones, which is also utilized for mouse genotyping.

The process has been industrialized, currently with an output of 5 to 6 modified alleles/week. The high-throughput nature of our process empowers its use as a direct genetic approach for target validation and assignment of gene function. Since the generation of knock-out alleles routinely employs the replacement of the gene of interest with reporter genes such as LacZ, we have developed a system for high throughput and high resolution gene expression profiling. The ability to generate both null alleles and to visualize expression patterns has empowered us to discover the functions of novel as well as previously known but uncharacterized genes. Examples from a variety of projects will be presented: (a) Knock-outs of genes involved in angiogenesis, metabolic pathways, neuroendocrine function, immune system, muscle, bone, and cartilage biology along with expression profiling; (b) conditional knock-out or transgenic alleles; (c) replacement of mouse gene with its human counterpart.


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