The cryptochrome mutation causes a small segment on the "tail" of the protein to get left out, and Partch's lab found that this changes how tightly cryptochrome binds to the CLOCK:BMAL1 complex. This feedback loop is the central mechanism of the biological clock, driving daily fluctuations in gene activity and protein levels throughout the body. Two of the clock proteins (CLOCK and BMAL1) form a complex that turns on the genes for the other two (period and cryptochrome), which then combine to repress the activity of the first pair, thus turning themselves off and starting the cycle again. The mutation affects a protein called cryptochrome, one of four main clock proteins. "We still have a lot to understand about the role of lengthened clock timing in delayed sleep onset, but this one mutation is clearly an important cause of late night behavior in humans." "This genetic marker is really widespread," Partch said. So the discovery of a relatively common genetic variation associated with a sleep phase disorder was a striking development. Sleep behavior is complex - people stay up late for many different reasons - and disorders can be hard to diagnose. How often this particular mutation is involved in delayed sleep phase disorder remains unclear, Partch said. The genetic variant identified in the 2017 study, however, was found in around one in 75 people of European descent. They are important to scientists as clues to understanding the mechanisms of the clock, but a given mutation may only affect one in a million people. Most of the mutations known to alter the clock are very rare, Partch said. A shortened clock cycle causes people to go to sleep and wake up earlier than normal (the "morning lark" effect), while a longer clock cycle makes people stay up late and sleep in (the "night owl" effect). Genetic variations that change the clock proteins can alter the timing of the clock and cause sleep phase disorders. "This mutation has dramatic effects on people's sleep patterns, so it's exciting to identify a concrete mechanism in the biological clock that links the biochemistry of this protein to the control of human sleep behavior," said corresponding author Carrie Partch, professor of chemistry and biochemistry at UC Santa Cruz.ĭaily cycles in virtually every aspect of our physiology are driven by cyclical interactions of clock proteins in our cells. The new findings, published October 26 in Proceedings of the National Academy of Sciences, reveal the molecular mechanisms involved and point the way toward potential treatments. In 2017, scientists discovered a surprisingly common mutation that causes this sleep disorder by altering a key component of the biological clock that maintains the body's daily rhythms. People with this condition are unable to fall asleep until late at night (often after 2 a.m.) and have difficulty getting up in the morning.
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