Genomic Timing

Our goal... is to define the biochemical machinery that underlies the mysterious yet ubiquitous process of circadian rhythmicity. Our entree into the process was the period (per) gene of Drosophila melanogaster.
— Michael Rosbash, "Molecular Genetics of RNA Processing and Behavior," HHMI Research in Progress, 1999.

This research provides direct evidence that clocks in mammals may be built with the same principles as those seen in fruit flies and fungi.
— Joseph Takahashi, referring to research on the mammalian Clock gene, NSF news release, 1997.

It is now three decades since the first known biological clock gene, per, was identified. Since that time, additional clock genes have been discovered in Drosophila, and clock genes have been discovered in organisms ranging from bread mold to mammals. The biochemical mechanisms that are responsible for the biological clockworks are beginning to be understood in detail. For most organisms studied so far, the clock mechanism seems to depend on a biochemical feedback loop that has a positive and a negative arm.

The first circadian gene to be cloned in mammals — a gene known as Clock — was cloned and sequenced in 1997. That same year, human and mouse versions of the per gene were identified.



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Drosophila melanogaster Genome Map, as Published in Science, March 24, 2000.
The per gene, whose location on the X chromosome is shown, is one of an estimated 13,600 genes (99% of which have been sequenced).


Click to watch the animation

The Chemical Tick Tock of a Drosophila Clock.
This animation sequence illustrates the major steps in the molecular feedback loop producing clock function in a Drosophila cell. It shows how four proteins — CLK, CYC, PER, and TIM — produce the core chemical oscillation that runs the biological clock. The proteins and the genes that produce them work in teams of two. The negative and positive feedback loops shown here rely on transcription, translation, and the binding of PER and TIM proteins — and are very similar in mammals.


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A Renowned Hamster — The Tau Mutant. In 1988, researchers discovered a Syrian hamster with a mutation — called tau — that caused its circadian clock to run fast. It was first circadian mutation to be identified in a mammal. Researchers have since cloned the tau gene and identified the enzyme, called casein kinase I epsilon, for which it encodes.


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Making Light of Circadian Rhythms — The Role of Photopigment Molecules. Cryptochromes in animals and phytochromes in plants are light-sensitive proteins that can transmit a signal containing information about light. Because cryptochrome has proven difficult to crystallize, its molecular structure is not fully known. This image represents a hypothetical structural model of Drosophila melanogaster cryptochrome. It was generated by comparing its amino acid sequence (purple, gray, and green structures) and two different chromophores (yellow, red, and blue structures) to that of a similar light sensitive protein found in bacteria (DNA photolylase) whose structure is known. Chromophores are the reactive centers of cryptochromes.


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Mouse Matters — Per Turns Up in Mice. Per, the gene first found in Drosophila, is also found in mice and other mammals. In mice, the Per1 gene is located on chromosome #11 (shown here in yellow). Usually, researchers are able to track a gene that has been found in one organism to other organisms by searching for corresponding sequences. That method did not work for mammalian Per, because the sequences did not directly correspond to those of Drosophila per.To date, three variants of mammalian Per have been identified.

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