CHEMICAL MUTAGENESIS IN MOUSE CIRCADIAN RHYTHMS

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Circadian rhythms which are driven by endogenous clocks with a period of approximately 24 hr under constant condition are observed in almost all creatures from procaryotes to mammals. The features of circadian rhythms are common to all species, but molecular mechanisms of circadian rhythms are unclear. The purpose of this study is to isolate circadian mutant in mice to understand molecular mechanisms of circadian rhythms. For this, we have used 3 different strategies. One is chemical mutagenesis, another is isolating a mutant from wild mice population and a third is a screening of inbred strains. Using this strategies, we have found several mutant mice which show abnormal rhythmicity. Furthermore, we have accidentally found another mutation in the course of breeding mice. The mutation found in wild mice population is characterized by loss of circadian rhythms under constant condition and shorter circadian period. Genetic analysis indicated that the arrythmic trait is recessive because … More F1 mice between the mutant and C57BL/6J show normal rhythms and the phenotype segregates in F2 and backcross. In the screening of inbred lines, CS mice were found to have abnormal circadian properties including longer free-running period, large activity phase, splitting of free-running rhythms in constant darkness. In order to identify chromosomal location of the genes influencing free-running period, we analyzed F2 progeny from the cross between CS and C57BL/6J mice by QTL (Quantitative trait locus) mapping method. As a result, three provisional regions on chromosomes 4 (LOD score=3.5), 12 (LOD score=3.4) and 19 (LOD score=3.7) were detected. These potential QTLs are investigated in another cross with MSM mice and it was found that the same region on chromosome 19 is detected with LOD score 4.2. These results suggest that the free-running period of CS mice is affected by multiple genes and particularly the QTL on chromosome 19 strongly affect the period. The last mutation found during the crossing of mice is characterized by suddenly disorganized rhythm and sometimes 8 hr periodicity under constant darkness. For future studies, this mutant mice were maintained with an appropriate breeding method. Less