How Genetics Impact Sleep
While sleep would seem to be an easy thing to understand, for we spend about one-third of our lives doing it, in actual fact sleep remains quite a difficult thing to define, and a still harder thing to scientifically research. In recent years, much research has tried to identify the genetic foundations of human sleep disorders, focusing upon some key areas of our genetic make-up in order reach important conclusions.
Circadian Clock Genes
Within each human exists a ‘clock’, something that regulates our sleep patterns and makes us feel either sleepy or wide-awake. Scientists have expected that in people with sleep disorders there might be something called ‘clock mutants’, that is, things which are broken or wrong in this internal clock. However, it is not as simple as that. For example, some patients might have something wrong with their homeostatic controls, rather than their circadian clock. Others might have something irregular in the way that their core clock proteins are produced. Overall, this will have an impact on the circadian period although specific diagnosis is needed in order to determine what the problem is.
Diabetics will often suffer from sleep disorders, while people with obesity might have short durations of sleep. Some have suggested that there is a link between these two categories. While not that much is known at a molecular level, recent research has investigated flies. When deprived of food, they sleep less; however, they do not then necessarily have a stronger desire to sleep. Specific proteins within them actively suppress sleep, and so the conclusion has been drawn that these proteins may be activated depending on diet, and whether one is over or under eating.
A well-known hypothesis has been made with regard to immune genes. According to this, immune genes actually encourage sleep. In particular, there is one immune protein which is ‘upregulated’ when mammals are suffering from sleep deprivation, and during sickness sleep is usually increased. Some immune genes may promote sleep when a person is responding to injury or infection. Therefore, under certain circumstances immune genes may promote sleep given certain pathological conditions, and so we can see sleep’s role in facilitating recovery. Equally, scientists have tried mutating some immune genes in Drosophila and zebrafish, which has increased daytime activity, again showing the link between genetics and sleep.
Genetic Factors Underlying Circadian Rhythm Disorders
It is undisputed that Familial Advanced Sleep Phase Syndrome (FASPS) is caused by mutations in human clock-related genes. Individuals who carry this ‘autosomal dominant trait’ have regular sleep patterns, and a whole-life inclination to awaken and go to sleep at extremely early times. Melatonin and temperature rhythms are advanced by 4–6 hours, and the free running period (i.e., the period of rhythms observed in the absence of any environment clues, which indicate an internal ‘clock time’) has been measured as 1 hour shorter than in controls. Underlying genetic mutations are seen as the cause of this.
Genetic Factors Regulating EEG (electrical activity) and the Sleep Homeostat
Genetic analysis of selected EEG (electrical) traits and the sleep homeostat is an active field in model systems and in humans. In studying mice, a single enzyme was noticed to be deficient, an enzyme which is involved in short chain fatty acid metabolism (ACADS). This shows the strong effect that genetic background has on the effect size of an identified gene, thus making it slightly difficult to pinpoint exactly which enzyme is deficient because it is species specific; it cannot simply be made into a rule.
Genetics of Human Narcolepsy-Cataplexy
Narcolepsy is an affliction which influences one’s control over sleepiness and wakefulness, resulting in tiredness in the daytime, with symptoms of dissociated REM sleep, ie. hallucinations and sleep paralysis. It can lead to disrupted sleep at night, and cataplexy (brief episodes of muscle weakness triggered by emotions). In animal tests, this condition can be replicated by disrupting hypocretin neurotransmission. However, in humans it is more sporadic and involves thousands of neurons rather than single gene mutations.
Restless Leg Syndrome
Restless legs syndrome (RLS) is a not uncommon disorder in which one has an uncomfortable and unstoppable urge to move one’s lower limbs. The symptoms are manifested during times of rest, are worse in the evening, and improve with movement. Leg movements in sleep are often also present. Many studies have concluded that iron deficiency in the brain and reduced dopaminergic neuronal activity are crucial pathophysiological factors. RLS has an undeniable genetic component, with up to 60% of cases reporting similarly affected family members.
Hypersomnias, Insomnia, and Parasomnias
Further sleep disorders, such as those mentioned above, show genetic effects or familial clustering, but no particular genes are yet implicated. Insomnia runs in families and, interestingly, has higher concordance in monozygotic twins, but this heterogeneous phenotype will depend on large samples and potentially EEG-based endophenotypes for genetic mapping. The research is still ongoing, and it will take further studies to make more comprehensively proven conclusions.
Sleep Disordered Breathing and Obstructive Sleep Apnea
Obstructive sleep apnea is a sleep disorder characterized by intermittent upper-airway collapse, which impairs ventilation and disrupts sleep. Various genetically influenced or physiologic factors may contribute to upper-airway collapse, such as anatomical features (e.g., craniofacial features), reduced dilator muscle activity during sleep, decreased end-expiratory lung volume, ventilatory control instability, and sleep-state instability, although obesity may outweigh these other predispositions.
It is abundantly clear that sleep is genetically controlled. Although environmental factors have an impact on the duration and quality of sleep, genetic regulation is demonstrated by the heritability of sleep traits, the identification of particular genetic polymorphisms that affect these traits, and the existence of familial sleep disorders. Genetic model systems –zebrafish, fruit flies and worms – have only recently been developed for studying sleep, and are starting to reveal the molecular foundations of sleep. This is a very interesting area in which we are scratching the surface. Given that we spend a third of our lives asleep, unlocking the secrets of this mysterious realm may help us in treating many genetic abnormalities in the years to come.