Genetic Basis Related to Circadian Abnormalities

A circadian rhythm is an internal self-sustained clock in nearly all organisms, which operates at the cellular level and regulates normal sleep patterns over a 24 hour period in response to consistent cycles of light and temperature. This internal clock is responsible for what we consider to be a "normal sleep schedule," which typically consists of an 8 hour sleep period ranging from around 22:00-07:00 each night. 

In Dr. Dan Cavanaugh's presentation, he discussed his research on the genetic implications of an abnormal circadian rhythm, as found in Drosophila melanogaster. In order to study the effects of an aberrant circadian rhythm, Cavanaugh and his team of researchers exposed the fruit flies to 4 hour phase delays in lighting conditions, producing an abnormal response of the circadian rhythm. This process resulted in a significant reduction in the median lifespans of these flies and a decrease in locomotor activity, regardless of their diets. After identifying the behavioral changes, researchers studied the molecular effects of chronic circadian misalignment (CCM). They discovered a significant change in the expression of several genes (whether upregulated or downregulated) which all function in the regulation of lipid metabolism, causing age-related decline. 

But are there underlying genetic causes of an aberrant circadian rhythm? Researchers at Rockefeller University studied patients with a common type of insomnia called delayed sleep phase disorder (DSPD), which causes them to consistently fall asleep several hours later and/or have more fragmented sleeping periods than a typical person with a normal circadian rhythm. This study showed that these "night owls" entered salivary dim light melatonin onset (DLMO) 5-7 hours later than the control who displayed a normal circadian rhythm. Researchers turned to the patients' DNA in attempt to identify a cause for this sleep disorder, and found a genetic mutation that causes a deletion of a portion of the tail of a Cry1 gene, which encodes a protein that is known to inhibit the activity of core circadian proteins CLOCK and BMAL.  In order to confirm the correlation of the Cry1 mutation and abnormal circadian rhythm, family members' DNA was observed, and researchers found the same mutation in all family members that reported frequent sleep problems. This suggests not only that the mutation is hereditary, but also that the Cry1 genetic mutation likely plays a large role in the development of DSPD in humans. 

These two studies both explore the genetic mutations and changes in genetic expression relating to aberrant circadian rhythms. The Rockefeller study shows the underlying genetic causes for a chronic circadian rhythm abnormality, while Cavanaugh's research shows the genetic implications of a chronic circadian misalignment. This allows researchers to understand the effects of a chronically abnormal sleep schedule at the molecular level, as well as understanding some possible underlying genetic causes for these atypical sleep schedules which may eventually lead to the discovery of a cure.

Link to article: https://www.cell.com/cell/fulltext/S0092-8674(17)30346-X