Genetics of the human circadian clock and sleep homeostat

Abstract

Timing and duration of sleep are controlled by the circadian system, which keeps an ~24-h internal rhythm that entrains to environmental stimuli, and the sleep homeostat, which rises as a function of time awake. There is a normal distribution across the population in how the circadian system aligns with typical day and night resulting in varying circadian preferences called chronotypes. A portion of the variation in the population is controlled by genetics as shown by the single-gene mutations that confer extreme early or late chronotypes. Similarly, there is a normal distribution across the population in sleep duration. Genetic variations have been identified that lead to a short sleep phenotype in which individuals sleep only 4-6.5 h nightly. Negative health consequences have been identified when individuals do not sleep at their ideal circadian timing or are sleep deprived relative to intrinsic sleep need. Whether familial natural short sleepers are at risk of the health consequences associated with a short sleep duration based on population data is not known. More work needs to be done to better assess for an individual's chronotype and degree of sleep deprivation to answer these questions.

Fig. 1

a Phase response curve to a pulse of light. b The impact of light on circadian phase based on time of delivery throughout the 24-h day relative to timing of dim light melatonin onset and core body temperature

Fig. 2

Typical sleep period timing compared with delayed sleep phase, advanced sleep phase, and natural short sleep

Fig. 3

Diagram of the relationship between familial advanced sleep phase (FASP), advanced sleep–wake phase disorder (ASWPD), and ASP of Aging. This figure is adapted from a figure that is reprinted with permission from the journal SLEEP [31]. Relatives sizes do not reflect relative prevalence as the prevalence of ASP of Aging is not known

Fig. 4

A conceptual framework for the relationship among different aspects of biology leading to innate traits of sleep timing and duration. These genetic factors interact with environmental factors such as electric lights, chemicals (ethanol, caffeine, medications), and familial and societal responsibilities which together may manifest as sleep duration and timing different from that programed by genetics. The relative contribution of each component is likely variable and remains under investigation