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Out of the loop:
New evidence for the complexity of biological clocks in mice
Edward R. Winstead

Researchers in the last decade have identified nine genes that are the core components of the mouse biological clock. Additional genes and polymorphisms in these genes are likely to account for the variation in the daily cycles of sleep and activity seen in different strains of mice, according to a new study of circadian rhythms in crossbred mice.

Joseph S. Takahashi, a Howard Hughes Medical Institute investigator at Northwestern University in Evanston, Illinois, and colleagues have identified 14 chromosomal regions that contribute to variation in circadian behavior in mice. The 14 regions, or genetic loci, may affect an animal's sense of biological time directly or through interactions with other genes, according to statistical analyses reported in a recent issue of Genome Research.

"This genetic analysis has revealed previously undetected complexity in the circadian system and points to the presence of many as yet undiscovered genes that contribute to the expression of this behavior in mice," the researchers write. "[I]t is possible that the broad variety of circadian behavior observed in mammalian species, including humans, is the result of polymorphisms in multiple, interacting loci such as the ones described here."

To characterize genetic polymorphisms affecting circadian rhythms in the mouse, the researchers used a strategy they call 'genome-wide genetic interaction analysis.' They measured five aspects of circadian behavior in crossbred mice, and then used algorithms to screen the data for potential locations of clock-related genes.

Gary A. Churchill, a statistical geneticist at the Jackson Laboratory, in Bar Harbor, Maine, led the computational analysis. Nine of the 14 loci uncovered by the genetic interaction analysis were not seen using conventional genome scanning methods.

The 14 loci appear to be largely distinct from the nine known circadian genes. Takahashi and colleagues mapped five of the proposed nine clock genes to locations on mouse chromosomes for the first time. The locations of the remaining four genes had previously been reported in the literature. Only one of the 14 new loci mapped closely to the location of a known circadian gene.

Models of biological clocks suggest that the core mechanisms are 'feedback loops' of interacting genes and proteins. These interactions regulate the expression of certain genes at different levels during a 24-hour period. As others have previously proposed, the researchers suggest in their paper that these genes are unlikely to be the only genetic factors underlying circadian behavior.

Although a feedback loop with a limited number of components may be sufficient to generate a rudimentary circadian rhythm, they write, "a variety of other proteins are likely to be involved in refining and amplifying this basic circadian oscillation."

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Shimomura, K. et al. Genome-wide epistatic interaction analysis reveals complex genetic determinants of circadian behavior in mice. Genome Res 11, 959-980 (June 2001).

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