Summary: New research from Rockefeller University links a common variant of the CRY1 gene to delayed sleep timing. People who carry this “night owl” mutation have a longer circadian cycle and tend to fall asleep and wake later than most.
Source: Rockefeller University
Many lifelong night owls may owe their late-night habits to a genetic change.
Scientists at Rockefeller University report that a variant of the circadian clock gene CRY1 slows the internal biological clock that regulates daily sleep‑wake timing. This change lengthens the circadian period for carriers, shifting sleep onset and wake time later than usual. The team published their findings in Cell on April 6, 2017.
“Compared with other mutations that have been linked to sleep problems in single families, this CRY1 variant represents a substantial genetic effect,” says senior author Michael W. Young, the Richard and Jeanne Fisher Professor and head of Rockefeller’s Laboratory of Genetics. The mutation appears to be relatively common in some populations—potentially present in about one in 75 people of non‑Finnish European ancestry.
Delayed sleep phase disorder and the impact of late sleep timing
The Centers for Disease Control and Prevention estimate that tens of millions of U.S. adults have sleep or wakefulness disorders. These conditions—ranging from insomnia to narcolepsy—can increase risk for chronic illness such as diabetes, obesity, and depression. One frequently reported pattern is delayed sleep phase disorder (DSPD), in which an individual’s preferred sleep window is shifted later than the societal norm.
People with DSPD commonly report being alert well into the night and struggling to fall asleep at conventional times. Consequently they are often required to wake before their bodies are ready for work, school, or other obligations, producing early‑night insomnia and daytime fatigue.
Studying free‑running sleep cycles to identify genetic causes
Young’s lab has investigated circadian biology for decades and has identified many core clock genes that coordinate daily rhythms of sleep, eating, hormones, and metabolism. To explore whether known circadian genes might underlie DSPD, the Rockefeller team, together with collaborators at Weill Cornell Medical College, enrolled study participants who spent two weeks living in a laboratory apartment isolated from time cues. Participants could sleep and eat whenever they wished while researchers measured their body temperature, hormone rhythms, and collected skin biopsies for cellular analysis.
Under such “free‑run” conditions, most people maintain a roughly 24‑hour sleep‑wake rhythm. One participant diagnosed with DSPD stood out: their intrinsic cycle was approximately 30 minutes longer than typical, and physiological markers that follow the clock—such as melatonin secretion—were delayed by several hours. “Melatonin often starts to rise around 9 or 10 p.m. in most people,” Young notes. “In this participant, melatonin did not increase until 2 or 3 a.m.”
A CRY1 mutation linked to later sleep timing
Genetic analysis of that participant revealed a variant in the CRY1 gene, a known regulator of the molecular circadian clock. In the normal clock, CRY1 protein helps suppress a group of clock genes during part of the daily cycle. The mutation identified by the researchers increases CRY1’s inhibitory activity, prolonging the period during which other clock genes are repressed. This gain‑of‑function effect lengthens the molecular circadian period and provides a direct mechanism for the delayed sleep phenotype.
Follow‑up family studies found five relatives who carried the same CRY1 variant; all showed signs of DSPD or a history of persistent sleep timing problems. Extending the search to genetic databases and clinical cohorts, the team identified additional unrelated carriers, including dozens from Turkey. Interviews and questionnaires indicated that 38 people with the mutation reported altered sleep timing, while family members without the mutation did not show unusual sleep patterns.
Analysis of large population databases suggests the allele frequency may be as high as about 0.6% (roughly one in 75) among people of non‑Finnish European descent. The mutation behaves dominantly, meaning that one copy is sufficient to shift sleep timing in carriers.
Implications for diagnosis and therapy
At present, the researchers do not recommend routine genetic testing for CRY1 among DSPD patients because identifying the causal change does not by itself provide an immediate cure. However, understanding the molecular mechanism raises the possibility of future therapeutic strategies that target the enhanced inhibitory function of the mutant CRY1 protein.
In the meantime, many people with DSPD can improve sleep timing through behavioral strategies: strict schedules, timed bright light exposure during the day, and other circadian‑based interventions often help shift the sleep window earlier. “There are behavioral tools we can use before turning to pharmaceuticals,” Young observes.
The research team plans further studies to determine whether CRY1 mutations also influence metabolic rhythms, since the human circadian system coordinates not only sleep but also hunger, hormone levels, and metabolite cycles.
Article author: Katherine Fenz, Rockefeller University
Original study: “Mutation of the Human Circadian Clock Gene CRY1 in Familial Delayed Sleep Phase Disorder,” by Alina Patke, Patricia J. Murphy, Onur Emre Onat, Ana C. Krieger, Tayfun Özçelik, Scott S. Campbell, Michael W. Young. Published in Cell, April 6, 2017.
Abstract (condensed)
A dominant coding variation in the core circadian clock gene CRY1 was identified in families with hereditary delayed sleep phase disorder. This gain‑of‑function allele increases CRY1’s inhibitory interaction with circadian activator proteins Clock and Bmal1, reduces expression of key transcriptional targets, and lengthens the period of molecular circadian rhythms. Reverse phenotyping of unrelated carrier families corroborates late or fragmented sleep patterns, suggesting this variant affects sleep behavior in a notable subset of the population.