Wednesday, February 27, 2013

Excerpts From: Clocks, Genes and Sleep

Core components of the circadian transcriptional clock. Brain-and muscle ARNT-like protein (BMAL1) heterodimerizes with CLOCK protein to bind E-box motifs in the promoter regions of downstream target genes, such as Period (Per 1,2) and Cryptochrome (Cry1,2) genes. PERIOD proteins (PERs) heterodimerize with CRYPTOCHROME proteins (CRYs) in order to inhibit CLOCK:BMAL1, thus closing an autoregulatory negative-feedback loop. Blocking activity of CLOCK:BMAL1 in Bmal1 knock-out mice disrupts normal circadian rhythms, and increases reactive-oxygen species (ROS), while concomitantly decreasing memory and lifespan. Circadian clock output regulates a variety of biological and physiological processes, including circadian rhythms, metabolism, learning and memory, ROS/reactive nitrogen species (RNS) homeostasis, aging and longevity, and the cell cycle.

by Malcolm von Schantz, PhD and Simon N Archer, PhD. Journal of the Royal Society of Medicine, Oct. 2003

Genes and Molecules

Information on how circadian rhythms are generated at molecular level comes mainly from studies in mice. The mechanism depends on tightly controlled concerted coexpression of specific clock genes.

Most of these genes are remarkably conserved amongst coelomates — including insects, molluscs and vertebrates — although the precise roles of specific components have drifted during evolution.

At the center of the machinery in mammals are the Period (Per1, Per2 and Per3) and Cryptochrome (Cry1 and Cry2) genes. The protein products of all these oscillate over the 24-hour cycle by inhibiting their own promoters operating in an intricate negative feedback loop.

Sleep Disorders

Sleep has famously been described as being ‘of the brain, by the brain, and for the brain’. Its relation to the circadian clock is less simple to describe. Some disorders of sleep are unrelated to circadian rhythms; others are undoubtedly related to it, particularly the advanced and delayed sleep phase syndromes. In these conditions, sleep occurs either abnormally early or abnormally late. This could theoretically be caused either by an abnormal τ or by abnormal timing of the sleep phase within a circadian cycle of normal periodicity.

Polymorphisms in clock genes can be related to circadian parameters, and the most famous finding so far is a large family where advanced sleep phase syndrome seems to be inherited as a single-gene defect. The condition manifests itself in this family with advanced melatonin, temperature, and sleep/wake rhythms co-segregating with a missense mutation in the Per2 gene. Because of the non-homologous aminoacid substitution, the resulting PER2 protein is phosphorylated less efficiently by casein kinase than the native one—an observation that offers a satisfying mechanistic explanation for the similarity between this phenotype and that of the τ hamster, whose missense mutation in casein kinase I ε results in essentially the same net effect.

Morning and Eveening Preferences

The gene associated with evening preference that has produced the most interesting results to date in humans is Per3. In a Japanese population, Ebisawa and colleagues reported that a rare single-nucleotide polymorphism causing an aminoacid substitution correlated with delayed sleep phase syndrome.

Our laboratory has studied a more dramatic genetic polymorphism, initially described but not characterized in Ebisawa's paper, encoding an 18-aminoacid tandem repeat sequence, of which humans have either four or five successive copies in each of their Per3 alleles.

By comparing HO-characterized subjects whose scores were around the mean for their gender and age group with those with extreme evening and morning preference, we were able to distinguish an excess p+revalence of the shorter repeat allele in subjects with extreme evening preference. Extending the study to a cohort of patients with delayed sleep phase syndrome, we showed that the association with the shorter allele was even stronger in this population. Thus, although no physiological studies have formally linked the extremes of evening preference and/or long τ with delayed sleep phase syndrome, it would appear from the convergence of their Per3 genotype that such a study is not only worthwhile but long overdue.


In man, the known human clock gene differences appear merely to predict a greater or lesser propensity.

One reason for this difference is that most of the mouse models studied so far have been engineered to abolish the function of a specific gene, rather than carrying a more or less altered form of it. Another is that laboratory rodent strains are highly inbred and thus much more homogeneous with respect to all other clock genes.

The human circadian genotype, being a polygenic trait, is more akin to a hand of cards. Most of us will have a hand containing average cards or a balanced mixture of high and low ones. Only the hands that contain predominantly low or high cards will stand out.

The great majority of us function normally with our allotted circadian phenotype and its interaction with our environment, much as we are able to deal with other aspects of our genetic inheritance.

But the minority who have been dealt a dud hand of the clock genes card game deserve more sympathy and clinical help than they are often accorded.

Our culture trends to associate early waking with virtue and industry, and late sleeping with vice and lassitude. Lack of conformity with this norm is not always a matter of choice: clearly, some people are genetically programmed for an extreme diurnal preference.

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