Vitaterna MH, King DP, Chang AM, Kornhauser JM, Lowrey PL, McDonald JD, Dove WF, Pinto LH, Turek FW, Takahashi JS. Science. 1994;264(5159):719-25.
Using the mutagenic agent, N-ethyl-N-nitrosourea, a mutated lineage of mice was generated with an inheritable phenotype of altered circadian rhythmicity. Wildtype mice maintained normal circadian rhythms in constant darkness with a period of 23.3 – 24 hours, whereas mice heterozygous for the mutation showed a lengthening of the circadian period to approximately 24.4 hours in constant darkness. Homozygous mutant offspring showed the greatest change in circadian phenotype, with an endogenous period of 26-29 hours in the initial weeks under constant dark conditions, after which the animals became arrhythmic.
This genetic mutation was mapped to the midportion of mouse chromosome 5, identifying the novel circadian gene, clock, a key factor regulating the circadian clock system.