Scientists report a genetic mutation, appropriately called "after-hours" (Afh), which affects our internal body clock and might help explain why some of us are “evening people”, only falling asleep in the early hours of the morning. The research has important implications for human health in an increasingly 24/7 culture, where shift work and continental travel (and the associated jet lag problems) are already linked to several diseases. It can also be important for the many brain disorders, such as dementia, bipolar disease and mental retardation, which are associated to disruptions in the sleep/awake cycle.
The earth moves on a 24-hours cycle and also (roughly) all plants and animals. This is the result of our internal body clock that follows a circadian pattern (circadian means “approximately one day”) and controls the physiological processes of all living organisms. The heart of the clock is located in the hypothalamus and regulation of the body is done through a range of hormonal and neural signals in response to direct input from the retina. By anticipating the living conditions, biological clocks allow animals to achieve maximum fitness through a better exploration of their environment, whatever finding food, reproducing or just being awake during those hours when the sun is out, allowing, for example, vitamin D production by human skin cells.
But in our society, characterised by increasingly altered sleep/awake rhythms, a 24-hour endogenous cycle can become a disadvantage and lead to disease when constantly disturbed. And in fact, night shift workers are believed to have increased levels of cancer probably due to constant tiredness, which is known to affect the immune system. As consequence, to understand how the internal body clock works and what are the genes involved in the process is crucial for human health.
With this aim Sofia I. H. Godinho, Elizabeth S. Maywood, Patrick M. Nolan and colleagues at the Mammalian Genetics Unit in Harwell, Oxfordshire, the MRC Laboratory of Molecular Biology, Hills Road, Cambridge and the New York University School of Medicine, USA have been monitoring randomly mutated mice looking for alterations in their daily rhythm so they could then identify the mutated circadian genes.
And in the study now published the team of researchers report the discovery of mice with abnormally long circadian periods, lasting approximately 27 hours, in contrast with the 23.6 hours cycle of normal mice. Through animal crossing and genetic analysis Godinho, Maywood, Nolan and colleagues managed to find that the mutation, which they called “after-hours” (Afh), was located in the gene Fbxl3, a gene until now not known to be linked to the circadian cycle. A second study lead by Michele Pagano of the New York University School of Medicine, USA, published in the same issue of Science, showed that the Fbxl3 binds and drives the degradation of a clock protein called Cryptochrome (CRY).
In fact, the internal body clock functions as a collection of biochemical reactions where circadian genes exist in a constant regulatory loop of positive and negative feedbacks. The protein CRY is part of one of those circadian loops together with another protein called Period (PER) and the genes Clock and Bmal1. These two genes –part of the first circadian genes to be identified in mammals - produce transcription factors (transcription factors are proteins that bind DNA inhibiting or activating genes) that activate PER and CRY production. As these two proteins accumulate within the cell they inhibit Clock and Bmal1 activity and consequently also their own production. As the day progresses PER and CRY are degraded releasing the inhibition and again leading to the production of transcription factors, more CRY and PER and so on in constant cycles.
Following Pagano and colleagues’ observations Godinho, Maywood and colleagues looked at CRY protein in Afh mutated mice to find that these animals had a much slower CRY degradation rate what could explain the longer circadian cycles.
In conclusion, the work by Godinho, Maywood and colleagues identifies Fbxl3 as a new gene involved in the mammalian circadian rhythm and shows that the mutation Afh by disrupting CRY protein degradation, delays the circadian regulatory loops and, in this way, extends the circadian cycle of mutated animals. Now, using these results and by relying on the homology of mammals genes the next step is to find the corresponding gene/mutation in humans and its association with disease.
As Godinho, a Portuguese scientist and one of the first author of the work says, “Once we identify an abnormal gene we can then proceed to study the human homologue by screening the extreme types in the human population looking for defects in the same gene. Once this has been established, pharmaceutical companies may then use this information to study this class of genes and proteins as potential therapeutical targets”
And in a society moving steadily towards a 24/7 culture, where abnormal daily rhythms are becoming the norm, to understand the complex genetics behind circadian systems is no doubt becoming more and more relevant to human health, behaviour and quality of life.
Reference: Science magazine advanced online edition 2007 “The After-Hours Mutant Mouse Reveals a Role for Fbxl3 in Determining Mammalian Circadian Period”
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