Diurnal Cycles and Genes

[Guest guest]

Here are a few reports on the discovery of a special gene which plays a

central role in helping to regulate the diurnal (daily) cyle of waking and

sleeping.

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http://www.personalmd.com/news/a1997051607.shtml

Clock Gene Controls Daily Cycle

NEW YORK, May 16 (Reuters) -- For the first time, researchers have discovered

a gene in mice that controls circadian rhythms, the cyclical variations that

mark the ebb and flow of daily life, including waking and sleeping and the

rise and fall of blood pressure, hormones, heart rate, and other factors.

Hopefully the finding may shed some light on human problems linked to daily

rhythms, such as sleeping disorders, jet lag, difficulty adjusting to shift

work, and sleeplessness encountered in old age. Scientists hope that the

findings may one day lead to treatment for these problems.

" There are certain human conditions where this work could eventually be

relevant, " said lead study author Dr. ph Takahashi, professor of

neurobiology at Northwestern University in ton, Illinois. " It turns out

there are a number of sleep disorders that are involved in the timing of

sleep rather than the sleep per se. Some people may have altered clocks that

tell them to sleep at the wrong time, so that's why they have trouble

sleeping. "

Other health problems have been tied to biological rhythms. For example,

heart attacks are more common in the morning and asthma attacks strike more

often in the wee hours.

" It's too early to make any strong prediction, but a lot of physiological

events vary throughout the day, " he said.

Three other genes have been discovered in the past that control biological

rhythms, two in fruit flies and one in Neurospora, a type of fungus. However,

this is the first to be discovered in a mammal, and Takahashi and colleagues

are currently trying to locate the human equivalent of the gene.

The gene was discovered in mice with an abnormal circadian rhythm that causes

them to function on a 25-hour " day " when living in constant darkness, rather

than the roughly 24-hour cycle found in most other organisms, including

humans, according to two reports in the current issue of the journal Cell.

The researchers traced the problem to a mutation in a section of DNA 100,000

units long, a region that was dubbed the " clock " gene. Mice that had two

mutated copes of the gene -- one from each parent -- lived a 28-hour a day

cycle, while those with one copy of the gene, woke up, nibbled their mouse

chow and ran on their exercise wheel on the 25-hour cycle.

When Takahashi and colleagues inserted the normal clock gene into mouse

embryos with a clock mutation, the mice then reverted to a 24-hour clock so

they were in sync with the rest of the rodent world. The protein made by the

clock gene appears to act as a transcription factor, or a protein that has

the ability to turn on other genes. The gene mutation in the mice produced an

abnormal protein missing a chunk of its normal length, a section 51 amino

acids -- the building blocks of protein -- long.

The researchers found that the protein made by the clock gene was found at

high levels in the eyes and the hypothalamus (a section of the brain), two

areas of the body known to help regulate biological rhythms, based in part on

exposure to light. The hypothalamus contains a bundle of 10,000 nerve cells

called the suprachiasmatic nuclei (SCN), the " master biological clock " in the

brain. The clock gene is also expressed in other areas of the body, including

heart, lung, kidney, testes and ovaries, according to the report.

" This landmark discovery holds great promise for better understanding what

may be the genetic basis for individual differences in human sleep-wake

behavior, " said Dr. Czeisler, an associate professor at Harvard

Medical School and chief of the Circadian Neuroendocrine and Sleep Disorders

Section at Brigham and Women's Hospital in Boston. " It may further help to

clarify the pathophysiology of a number of circadian sleep disorders. "

SOURCE: Cell (1997;89:641-653)

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http://www.accessexcellence.org/WN/SUA10/clock597.html

The newly identified biological clock gene is located in a segment of some

100,000 DNA base pairs. It has 24 separate " exons, " or regions that code for

the protein. The sequence of the protein indicates it is a transcription

factor.

The Clock gene includes a DNA binding motif, an activation region, and sites

designed to interact with other proteins, called " dimerization domains. "

These features give important clues to how the circadian clock might

function in mice and humans.

" The fact that the Clock gene is a transcription factor provides direct

evidence that clocks in mammals may be built using a 24-hour program in which

genes are turned on and off once each day, " Takahashi said. Such a molecular

clock has been described in fruit flies and fungi, which were until now the

only organisms in which clock genes had been cloned and identified at the

molecular level........

The expression of the Clock gene was found to be very high in two tissues

known to be able to generate circadian signals, the eye and the

suprachiasmatic nucleus (SCN) of the hypothalamus. Surprisingly, Clock was

also found to be expressed in other areas of the brain as well as in other

tissues including the testis, ovary, liver, heart, lung and kidney. The

widespread expression of Clock leads to the speculation that Clock may

regulate the temporal organization at many different levels in cells and

tissues in the body.....

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Dr Mel C Siff

Denver, USA

http://groups.yahoo.com/group/Supertraining/