International Mammalian Genome Society

logo18th International Mouse Genome Conference

17-22 October 2004, Seattle, USA


Godinho SIH, Shaw-Andrews L, Clay J, Bacon Y, Nolan PM

MRC, Harwell, United Kingdom

Large scale mutagenesis screens have provided a powerful tool for the characterisation of behavioural mutants used in the study of gene function. Using the chemical mutagen N-ethyl-N-nitrosourea (ENU) we have screened approximately 2000 progeny of chemically mutagenised mice. Approximately 5% of all animals screened presented an abnormal phenotype with 1% showing robustly inherited mutant phenotypes.

Two mutant lines with dominant rhythm phenotypes will be presented here. One, Play 8 (short circuit, Sci) presents a reduced circadian amplitude, a short circadian period in constant darkness (21.4 to 23hrs) and a reduced phase shift in response to light. This phenotype is reminiscent of some features seen in familial advanced phase sleep syndrome. To date, intercrosses have been unsuccessful in identifying a homozygous phenotype. The mutant locus is a novel circadian locus between 106.9 and 110.5Mb on chromosome 8. A second mutant line, Play 68, presents a subtle but significant lengthening of the free-running period (24.3hrs compared to 23.6hrs in wt). No additional anomalies were observed in heterozygotes. Intercrosses revealed an additional class of phenotype in presumptive homozygotes. In light:dark conditions, activity onsets were delayed by approximately 5 hours and free-running period in constant darkness was approximately 27 hrs. Homozygotes display features of familial delayed sleep phase syndrome in humans. This mutant also maps to a novel circadian locus on chromosome 14, between 91 and 99Mb.

We are presently sequencing several potential candidate genes and undergoing fine mapping using additional polymorphic markers for both mutant lines. In addition we are studying the molecular expression of genes known to be expressed in the suprachiasmatic nucleus (SCN) which are closely involved in the regulation of circadian rhythms. Such mutants may ultimately provide an insight into human behaviour and neurological disorders.

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