International Mammalian Genome Society

logo18th International Mouse Genome Conference

17-22 October 2004, Seattle, USA


PLENARY PRESENTATION

MONDAY OCTOBER 18

2.15pm – 2.45pm

Contemporary approaches to extract gene function from the mouse genome

Bradley A

Wellcome Trust Sanger Institute, Cambridge,United Kingdom

The human and mouse genome projects have provided a product of extraordinary scientific value.  Of the estimated 25,000 genes, most have not been examined experimentally.

In parallel to the sequencing effort, enormous progress has been made in our ability to examine gene function in mice by generating and analyzing mutations.  To accelerate genetic analysis further we have been using chromosome engineering to develop genetic resources based on strategies originally developed in Drosophila, balancer chromosomes.  Our mouse balancers are tagged with coat colour genes enabling recessive mutations to be rapidly identified and maintained

The availability of the mouse genome sequence has enabled us to develop indexed reagents, allowing systematic approaches for generating knockouts and chromosomal rearrangements.  These reagents facilitate the rapid construction of knockouts.  100,000 vectors are displayed in the Ensembl genome browser (www.ensembl.org) under the DAS source MICER.  

Finally, I will describe a strategy which enables recessive genetic screens to be conducted in cultured ES cells, by-passing the time consuming step of producing and inter-crossing mutations in mice.  We have exploited the high rate of mitotic recombination in Blm-deficient ES cells to generate a genome wide library of homozygous mutant cells from heterozygous mutations induced with a revertible gene trap retrovirus.  We have screened this library for cells with defects in mismatch repair and demonstrate the recovery of cells with homozygous mutations in known and novel components of this system. The combination of insertional mutagenesis in Blm-deficient ES cells opens a new approach for phenotype based recessive genetic screens in ES cells.

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