Gene mutation upsets mammalian biological clock

April 20, 2000

Researchers have pinpointed the cause of a genetic mutation that switches a hamster's biological clock to a 20-hour day from the normal 24-hour day.

In the April 21, 2000, issue of the journal Science, Joseph S. Takahashi, a Howard Hughes Medical Institute investigator at Northwestern University, and his colleagues report that they have identified the enzyme encoded by the tau gene, the first single-gene circadian mutation to be discovered in mammals. In 1988, researchers first described the tau gene in Syrian hamsters that exhibited a shorter-than-normal biological clock.

"The tau mutant, arguably, has been one of the most significant genetic animal models for the study of circadian rhythms in mammals," said Takahashi. Identifying the cause of the tau mutation offers researchers a new tool for understanding biological clocks in humans, as well as a potential target for drugs that control the biological clock.

"With the cloning of tau the supply of mammalian clock mutants has been exhausted for the moment, but there is little doubt that many of the critical elements of animal clocks have been identified," writes Michael W. Young of The Rockefeller University in an editorial that appears in the same issue of Science.

Most biological clocks operate on a 24-hour, or circadian (Latin for "about a day"), cycle that governs such functions as sleeping and waking, rest and activity, fluid balance, body temperature, cardiac output, oxygen consumption and endocrine gland secretion. In mammals, the main components of the circadian clock are found in cells in the brain. Inside these cells, the molecular components of the clock are "rewound" daily by the effects of light and other stimuli.

Takahashi and his Northwestern colleagues, Phillip L. Lowrey, Kazuhiro Shimomura, Marina P. Antoch, and Peter Zemenides, with Shin Yamazaki and Michael Menaker at the University of Virginia, and Martin R. Ralph at the University of Toronto, used genetic and biochemical techniques to find the enzyme altered by the tau mutation.

"The discovery of the tau mutation by Ralph and Menaker more than a decade ago was extremely important because it was the first mutation shown to alter circadian rhythm in a mammal," said Takahashi. "The major problem in identifying the gene underlying this mutation was that it was found in Syrian hamsters, which were not among the model organisms addressed in the Human Genome Project." Thus, said Takahashi, genetic data and analytical techniques available for studies of mice and humans were not available for hamster studies.

To overcome these obstacles, Takahashi and his colleagues sought first to identify a wild-type Syrian hamster strain that was genetically distinct from all other Syrian hamsters in captivity. Syrian hamsters in captivity are the offspring of hamsters originally captured in 1929.

Once they found a wild-type hamster strain from a second capture made in 1971, they used a genetic subtraction method called genetically directed representational difference analysis to make detailed comparisons of the genes of the two strains of hamsters and offspring that resulted from crosses between the two strains.

Such comparisons enabled the researchers to identify specific segments of DNA associated with the tau locus. Using these DNA fragments, the scientists then isolated from collections of hamster genes larger DNA sequences that they compared to mouse and human genes. These comparisons showed that the hamster tau gene codes for CKIe(casein kinase I epsilon) -- a type of enzyme that had never before been associated with the machinery of the mammalian circadian clock.

Interestingly enough, however, Michael W. Young and colleagues at The Rockefeller University found that the Drosophila circadian mutation double-time is also encoded by a casein kinase I that is most similar to the epsilon form of mammalian CKI.

"Our results, from both genetic linkage analysis and molecular analysis of the specific gene mutation, provide definitive evidence that CK1eis a component of the mammalian circadian clock," said Takahashi.

The researchers then set out to find how the single amino acid substitutions in CK1e could shorten circadian rhythm. They found that subtle structural changes introduced by the substituted amino acid altered the enzyme's ability to function as a biochemical switch. The mutation rendered the enzyme slower at switching on proteins produced by a key circadian rhythm gene, called PERIOD, said Takahashi. The regular rise and fall in levels of these circadian proteins governs the length of each cycle of the biological clock. The alteration in CK1e effectively changes the animals' circadian rhythm from 24 to 20 hours.

According to Takahashi, the discovery of the CK1egene's role in circadian rhythms offers an unprecedented opportunity for developing drugs to control the biological clock in humans.

"We now know that there are nine genes governing circadian rhythms, eight of which code for DNA transcription factors or transcriptional regulators. CK1eis the only gene that codes for an enzyme, which is a lot easier to use as a drug target. Such drugs could conceivably shift a person's biological clock, enabling that person to more readily adapt to changing schedules due to travel or shift work, for example."

More speculative, said Takahashi, is the idea that drugs that control circadian rhythms might could be used to treat either seasonal affective disorder -- a depression caused by less natural light in winter -- or psychiatric disorders such as manic depression that seem to be associated with sleep disorders.

Howard Hughes Medical Institute

Related DNA Articles from Brightsurf:

A new twist on DNA origami
A team* of scientists from ASU and Shanghai Jiao Tong University (SJTU) led by Hao Yan, ASU's Milton Glick Professor in the School of Molecular Sciences, and director of the ASU Biodesign Institute's Center for Molecular Design and Biomimetics, has just announced the creation of a new type of meta-DNA structures that will open up the fields of optoelectronics (including information storage and encryption) as well as synthetic biology.

Solving a DNA mystery
''A watched pot never boils,'' as the saying goes, but that was not the case for UC Santa Barbara researchers watching a ''pot'' of liquids formed from DNA.

Junk DNA might be really, really useful for biocomputing
When you don't understand how things work, it's not unusual to think of them as just plain old junk.

Designing DNA from scratch: Engineering the functions of micrometer-sized DNA droplets
Scientists at Tokyo Institute of Technology (Tokyo Tech) have constructed ''DNA droplets'' comprising designed DNA nanostructures.

Does DNA in the water tell us how many fish are there?
Researchers have developed a new non-invasive method to count individual fish by measuring the concentration of environmental DNA in the water, which could be applied for quantitative monitoring of aquatic ecosystems.

Zigzag DNA
How the cell organizes DNA into tightly packed chromosomes. Nature publication by Delft University of Technology and EMBL Heidelberg.

Scientists now know what DNA's chaperone looks like
Researchers have discovered the structure of the FACT protein -- a mysterious protein central to the functioning of DNA.

DNA is like everything else: it's not what you have, but how you use it
A new paradigm for reading out genetic information in DNA is described by Dr.

A new spin on DNA
For decades, researchers have chased ways to study biological machines.

From face to DNA: New method aims to improve match between DNA sample and face database
Predicting what someone's face looks like based on a DNA sample remains a hard nut to crack for science.

Read More: DNA News and DNA Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to