The Genetics of the Human Circadian Clock

Daily rhythms of behavioral and physiological processes are believed to arise from endogenous circadian clocks. Unlike model organisms, genetic studies of human behavioral traits present extra challenges due to many factors such as the heterogeneous genetic background and environmental influences. Identifying molecular components of the human circadian clock were not possible until the recognition of Mendelian circadian traits in human subjects in recent years. Characterizing these rare Mendelian traits therefore established the foundation for identification of the genetic components for human circadian and sleep mechanisms. This line of investigation has proven fruitful and provided new insights into these pathways. Genetic association studies have also offered many possible genetic contributions to these mechanisms. Studies of these genes/proteins in conjunction with modeling human mutations in model organisms afford the opportunity to unravel the molecular mechanisms which in time will lead to pharmacological interventions that may not only help modify these behavioral traits but also may prove effective for treating other sleep-related disorders. Humans, like most organisms, exhibit daily rhythms in behavior and physiology. Jurgen Aschoff, one of the pioneers in the field of human circadian rhythms, demonstrated that these rhythms persist in (relatively) constant conditions with an approximately 24-h (i.e., circadian) periodicity (Dunlap et al., 2004). In one of his early studies, human subjects lived in a converted former bomb shelter underground without time cues or direct social interactions and could select their own sleep-wake schedules. The subjects exhibited an approximately 25-h rest-activity cycle as well as circadian oscillations of other physiological variables, suggesting the presence of an endogenous circadian clock. However, the mechanism for this endogenous clock remained largely unclear until some 30 years later when a culmination of data from animal studies suggested a transcriptional-translational feedback loop with a circadian period length (Hastings et al., 2008).