International Mammalian Genome Society

logo18th International Mouse Genome Conference

17-22 October 2004, Seattle, USA


McKeone R, Rowe C, Polley S, Wells S, Arkell R, Davies J, Bogani D, Dear N, Denny P

MRC Harwell, Didcot, United Kingdom

The Del(13)Svea36H (or Del36H) mutation is associated with a deletion of about 12.7 Mb of mouse chromosome 13.  Mice that are heterozygous for Del36H are viable and fertile and have been used to identify ENU-induced recessive-lethal mutations.

In order to facilitate positional cloning of these recessive mutations, sequence data from BAC clones has been used to generate a set of microsatellite markers across the Del36H region. These markers were then tested for polymorphism between each strain used in the screen.

To complement the lethal recessive screen, a gene-driven screen is underway to discover additional mutations of genes in the region. DNA from the F1 progeny of mutagenised individuals from the MRC Harwell ENU mutagenesis programme has been screened using dHPLC.  The first gene to undergo screening, Foxf2, is a forkhead family transcription factor gene.

A Trp to Arg mutation has been discovered in the DNA binding domain of Foxf2, which occurs within a potential -sheet structure. The tryptophan at this position is conserved in all members of the forkhead family and so may represent a critical residue.  Mice with this mutation have been rederived by in vitro fertilisation using cryopreserved spermatozoa from the ENU archive and outcrossed onto C3H.

Heterozygous mutant animals have undergone a battery of phenotype tests in order to detect dominant phenotypes associated with the Foxf2 mutation; so far, none has been uncovered.  Two homozygotes have been born, each dying several days after birth.  This is in contrast to the phenotype reported for mice homozygous for a null allele of Foxf2 produced by gene targeting, which die by 12 hours after birth.  It is possible that the ENU induced mutant allele is hypomorphic, contributing to observed longer survival time.

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