In a pedigree derived from a mouse treated with the mutagen ethylnitrosourea, a mutation has been identified that predisposes to spontaneous intestinal cancer. The mutant gene was found to be dominantly expressed and fully penetrant. Affected mice developed multiple adenomas throughout the entire intestinal tract at an early age.

Germ-line mutations of the APC gene are responsible for familial adenomatous polyposis (FAP), an autosomal dominantly inherited disease in humans. Patients with FAP develop multiple benign colorectal tumors. Recently, a mouse lineage that exhibits an autosomal dominantly inherited predisposition to multiple intestinal neoplasia (Min) was described. Linkage analysis showed that the murine homolog of the APC gene (mApc) was tightly linked to the Min locus. Sequence comparison of mApc between normal and Min-affected mice identified a nonsense mutation, which cosegregated with the Min phenotype. This mutation is analogous to those found in FAP kindreds and in sporadic colorectal cancers.

In a search for genes that regulate circadian rhythms in mammals, the progeny of mice treated with Nethyl-N-nitrosourea (ENU) were screened for circadian clock mutations. A semidominant mutation, Clock, that lengthens circadian period and abolishes persistence of rhythmicity was identified. Clock segregated as a single gene that mapped to the midportion of mouse chromosome † To whom correspondence should be addressed. * Present address: Department of Biological Sciences, Wichita State University, Wichita, KS 67260, USA.Published as: Science. 1994 April 29; 264(5159): 719-725. HHMI Author Manuscript HHMI Author Manuscript HHMI Author Manuscript5, a region syntenic to human chromosome 4. The power of ENU mutagenesis combined with the ability to clone murine genes by map position provides a generally applicable approach to study complex behavior in mammals.Progress has been made at the physiological and cellular levels in our understanding of circadian systems (1), yet the molecular mechanism of circadian clocks has not been fully elucidated (2). The isolation of "clock mutants" and the widespread requirement for protein synthesis in circadian clock systems imply that gene expression is an integral component of the oscillator (2). Recent molecular work with the Drosophila period (per) and Neurospora frequency (frq) genes suggests that a circadian cycle of per and frq transcription, respectively, may lie at the heart of the oscillator mechanism in these species (3). However, no information exists concerning the molecular elements of the clock system in mammals. In the absence of specific mechanistic information, genetics has been a powerful approach to uncover unknown elements. We report here the isolation of a mutation in the mouse that changes two central properties of circadian rhythms: the intrinsic period length and the persistence of rhythmicity. Taken together, our results define a gene, named Clock (for circadian locomotor out-put cycles kaput) that is essential for normal circadian behavior.Because the majority of clock mutants isolated in other organisms have been semidominant (4), we screened heterozygotes directly in the mouse. With the mutagen ENU, average forward mutation frequencies of 0.0015 per locus per gamete (1 in 700) can be achieved in the mouse (5). Male mice of the inbred strain C57BL/6J (B6) were treated with a single injection of ENU and after recovery of fertility were mated with untreated B6 females (6). First generation (G1) offspring would be heterozygous for any induced mutations but otherwise possess an isogenic B6 background (Fig. 1A). Normal B6 mice exhibit a robust circadian rhythm of wheel-running activity; we used this behavioral assay to screen for circadian mutants (Fig. 1B). Activity rhythms were monitored during exposure to a lightdark cycle (LD) to assess synchronization or entrainment behavior and in constant darkness (DD) to determine the circadian period of the locomotor activity rhythm (7). Laboratory mice typically have circadian periods of less than 24 hours, w...

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