GENETICS

Genes that keep us in bed

Study of the effects of noise on sleep. Researchers study the brain and cardiovascular reactions of sleeping subjects exposed to train, aeroplane or traffic noise. They also analyse how these nocturnal disturbances impact on cognitive performance and mood the next day. Noise fragments sleep and causes vegetative reactions in the cardiovascular system which, in the long term, can place people at higher risk of heart attack. Experiment conducted at the French National Center for Scientific Research (CNRS) in Strasbourg (FR). © CNRS Photothèque/Hubert Raguet
Study of the effects of noise on sleep. Researchers study the brain and cardiovascular reactions of sleeping subjects exposed to train, aeroplane or traffic noise. They also analyse how these nocturnal disturbances impact on cognitive performance and mood the next day. Noise fragments sleep and causes vegetative reactions in the cardiovascular system which, in the long term, can place people at higher risk of heart attack. Experiment conducted at the French National Center for Scientific Research (CNRS) in Strasbourg (FR).
© CNRS Photothèque/Hubert Raguet
Images taken from a 10-minute video of a fruit fly with a mutated Sleepless gene (on the right) and a ‘normal’ fly (on the left). The normal fly remains immobile during this 10-minute interval, while the mutant fly moves several times. In fact, fruit flies with a mutated Sleepless gene can sleep between 85% and 100% less per day. © Kyunghee Koh
Images taken from a 10-minute video of a fruit fly with a mutated Sleepless gene (on the right) and a ‘normal’ fly (on the left). The normal fly remains immobile during this 10-minute interval, while the mutant fly moves several times. In fact, fruit flies with a mutated Sleepless gene can sleep between 85% and 100% less per day.
© Kyunghee Koh

Do you sleep a little or a lot? It may surprise you to know that the amount of sleep you need depends on your genes. Although much is known about the genetic mechanisms that send us to the land of dreams, until recently far less was known about the mechanisms that determine the amount of time we spend sleeping. Now, research using the fruit fly as an animal model has pointed up a few key genes.

In his novel À la Recherche du Temps Perdu (In Search of Lost Time) Marcel Proust wrote that “one cannot pro perly describe human life unless one bathes it in the sleep into which it plunges night after night and which sweeps round it as a promontory is encircled by the sea…” Sleep, which has remained a constant of many species throughout their evolution, occupies a third of a person’s life. Why is it that, for millions of years, living beings have slipped daily into this state of partial unconsciousness that renders them so vulnerable?

Despite the vital and universal nature of sleep, this question has never been fully answered, and many of the mechanisms governing sleep are still a puzzle. Over the past 10 years or so, there has been a surge of research into sleep regulation, and molecular and genetic analysis techniques are evolving rapidly, gradually unveiling the mysteries of sleep. To discover how and why we fall asleep naturally each night, researchers are focusing their attention on the genetics of sleep. Identifying the genes involved in sleep regulation may not only provide answers to these fundamental questions, but also lead to new treatments for sleep disorders.

Deficit, clock and DNA

Sleep has a regulatory system enabling organisms to compensate for loss of sleep or surplus sleep (sleep homeostasis). The timing, duration and quality of sleep are regulated by two processes: a homeostatic mechanism and the circadian system. The homeostatic mechanism regulates sleep intensity, while the circadian clock (your internal biological clock) regulates the timing of sleep. A sleep deficit elicits a compensatory increase in the intensity and duration of sleep, while excessive sleep reduces sleep propensity. This explains why you need to catch up on your sleep the day following a sleepless night. Although the rhythm of the circadian clock is endogenous, it is reset regularly by daylight. “Sleep is regulated by the duration and quality of the preceding period of wakefulness, as well as by your circadian clock. When the sleep-wake cycle is normal, the circadian clock produces a cycle lasting about 24 hours and determines the optimal times for sleeping and being active. That is why we fall asleep more easily at night than during the day,” explains Tarja Porkka-Heiskanen, coordinator of the European Enough Sleep project, who is from the University of Helsinki’s Institute of Biomedicine (FI). This research project was completed in November 2008 and included 10 European partners involved in the study of homeostasis and sleep disorders.

Although all human beings are subject to these two major sleep regulation processes, there are wide variations from one person to another. Some people are happy with just five hours of sleep, while others are still tired after eight. The time we go to bed and the amount of sleep we need to function properly also depend on the individual. The reason is simple: sleep is genetically determined. “The electrophysiological ‘fingerprint’ of sleep (the electrical brain activity and physiological parameters recorded during sleep) is one of the most hereditary of all human characteristics. Sleep studies of twins have also shown that sleep timing and duration are genetically programmed,” says Tiina Paunio, researcher at Finland’s National Institute for Health and Welfare and head of genetic analyses in the Enough Sleep project.

Fruit fly to the rescue

So your DNA determines whether you are a morning lark or a night owl, as well as how much sleep you need. “Sleep duration and timing are both controlled by genes,” explains Amita Sehgal, professor of neuroscience at the University of Pennsylvania’s Howard Hughes Medical Institute (US), specialising in research into the genetic and molecular mechanisms that regulate circadian rhythms and sleep. “Several studies have shown that the mutation of certain genes in animals affects the duration or timing of their sleep. However, we know much more about the mechanisms and genes governing the timing of sleep than about those governing sleep duration,” adds Amita Sehgal.

Scientists have a key partner in their study of sleep regulation: the common fruit fly (Drosophila melanogaster). This little fly is one of the model organisms most commonly used in biological research – especially genetics. As fruit flies are small, easy to breed and have a very short generation time, they make the ideal guinea pigs for observing the effect of one or more gene mutations on behaviour. When, in 2000, two American research teams simultaneously discovered that the rest period observed in the fruit fly could be classed as sleep, this fly became a study model for the genetics of sleep. Surely it is a bit far-fetched to use a fly to try to understand human sleep? On the contrary, the authors of these two studies show that the fruit fly’s sleep patterns closely resemble those of humans. Just like humans, the fruit fly usually stays quiet and immobile for between 6 and 12 hours each night, during which time it loses most of its ability to respond to stimuli. When deprived of sleep, both humans and their winged counterparts will make up lost sleep the next night. Fruit flies also sleep more in their youth than later in life, when their sleep is fragmented, as with humans.

A sleep-depriving mutation

Although the genes that control the amount of sleep you need, and hence sleep duration, have been more reluctant to reveal themselves, they have not remained completely obscure. Several suspects have been identified in recent years. In 2005, a research team from the University of Wisconsin (US) discovered the role of the shaker gene in the sleep duration of fruit flies. This gene codes for the potassium channels that control the entry of the potassium ion (K+) into the cells, so determining the electrical activity of the neurons. While exploring the factors responsible for sleep duration, the scientists made a detailed study of some 9 000 mutant fruit flies. It was then that they happened across a line of fruit flies that sleep just one third the amount of time that ‘normal’ fruit flies sleep.

When they discovered that these shortsleeping mutants also manifested vigorous legshaking behaviour as they recovered from anaesthesia, the researchers turned their attention to the shaker gene that causes this effect. The genetic analyses revealed that the mutants’ shaker genes contained a single amino-acid mutation, which meant that a functional potassium ion channel could not be formed on the cell membrane, with the result that potassium could not flow through it. Apart from the direct link between this shaker gene variant and the short sleep duration of the fruit flies carrying it, another interesting feature of these stay-awake mutants is that they have a much shorter life expectancy than non-mutants.

This discovery, published in Nature, not only confirms the key role played by potassium flow in sleep regulation, as suggested in previous studies, but also points to the shaker gene as one of the key elements in the genetics of sleep. Can these observations be applied to human beings? We still have no confirmation that human genes and potassium ion channels are akin to those of the fruit fly. Now, though, researchers have upped their testing from fruit flies to mammals: “The shaker gene is also present in mice, and studies have shown that this gene affects their sleep too,” explains Amita Sehgal.

Sleep need, a question of excitability

In late 2007, a research team from the University of Lausanne’s Faculty of Biology and Medicine (CH) unveiled another key element in sleep genetics in Proceedings of the National Academy of Sciences. When different strains of mice were deprived of sleep, the researchers discovered that they did not all experience the same sleep need.

An analysis of the expression of all genes in the mice brains revealed that the Homer1a gene was the main gene responsible for differences in sleep need. This gene, which is also involved in the excitability of neurons, plays a key role in regulating intracellular calcium (Ca++). A state of wakefulness causes an inrush of calcium into the neurons to enable them to respond to the stimuli received, but an excess of Ca++ can become toxic to the neurons. According to the authors, sleep triggers the Ca++ regulation process via the Homer1a gene.

These results would explain both our sleep need and the fact that not everybody reacts to sleep deprivation in the same way. The Swiss researchers believe that this discovery would offer the first mole cular proof of the role of sleep in the process of brain protection and recovery.

In July 2008, Science published the results of a study by Amita Sehgal revealing the effect on the sleep of fruit flies of a mutation in a gene called Sleepless. This gene codes for a protein which, when released into the brain of fruit flies, reduces the excitability of nerve cell membranes and creates the need to sleep. Fruit flies with a mutated Sleepless gene, which were unable to produce this protein, slept between 85 % and 100 % less per day. Lastly, a new study by scientists from North Carolina State University (US), published in Nature Genetics in early 2009, has confirmed that fruit flies are ‘genetically programmed’ to sleep. The genetic analysis of 40 lines of fruit fly used for this research has led to the identification of some 1 700 genes responsible for sleep variability in fruit flies.The authors suspect that some of these genes are involved in the regulation of sleep duration.

Towards better hypnotic drugs?

“There is still much more we have to learn about the genetic regulation of sleep, such as the sequential organisation of the expression of sleep genes and the variability of their expression over time,” explains Tiina Paunio. Indeed, sleep does not remain constant over a person’s lifetime. Sleep disorders can appear with age, stress, or illnesses such as sleep apnoea or depression, altering the quantity or quality of this state so crucial to human physical and mental well-being. The aim of the recently completed European PROUST project was to press for the ‘time’ factor to be included in biomedical research as a fourth dimension of life. One strand of the PROUST project concerned the regulation of sleep-related genes over time.

Lack of sleep causes such effects as impaired cognitive performance and immune response, metabolic imbalances and diminished concentration. Understanding the function of sleep and the mechanisms that govern it could lead to the development of more targeted treatments for people with sleep disorders to replace the sleeping tablets they are currently prescribed, thereby improving their quality of life. Although recent scientific discoveries have illuminated some of the murky depths into which most ordinary mortals sink every night, it will be a long time before the experts can collect and assemble all the pieces in the jigsaw and finally lay their weary heads to rest.

Audrey Binet



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