People with advanced sleep phase trait find it difficult to stay up at night, but they also wake up very early in the morning, unable to fall back asleep. Identifying the genes underlying this sleep pattern can shed light on circadian biology.
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In the 1990s, a woman approached sleep neurologist Christopher Jones at the University of Utah with an unusual complaint. She would fall asleep very early in the evening and wake up for the day at 2AM. Her odd sleep schedule was preventing her from spending quality time with her loved ones.
When she told Jones that some other members of her family experienced a similar sleep pattern, he suspected a genetic cause. Hoping to get some answers, he reached out to Louis Ptáček, a human neurogeneticist at the University of Utah. They suspected that the woman suffered from advanced sleep-phase syndrome: a condition where people find it difficult to stay up at night and wake up very early in the morning, unable to fall back asleep. However, scientists did not understand the underlying disease biology.1
Louis Ptáček, a neurogeneticist studies the genetic basis of familial advanced sleep phase trait at UCSF.
Louis Ptáček
Finding a family with this trait was “exciting,” said Ptáček, now at the University of California, San Francisco (UCSF). “With familial traits, we’re able to use genetics to identify the causative gene and the causative mutation or genetic variant.”
In 1999, Jones and Ptáček examined people from the woman’s family and uncovered the inheritance pattern of this condition, which they dubbed familial advanced sleep-phase syndrome.2 Eventually, the researchers joined forces with Ying-Hui Fu, a human geneticist and sleep scientist at UCSF, to investigate the genetics of such sleep disorders. Their research has not only answered questions about this condition but also provided insights about the biology of sleep and circadian function.
The DNA Encodes Sleep Traits
To investigate whether the characteristic sleep pattern of the woman who approached Jones had a familial aspect, Jones and Ptáček evaluated affected and unaffected people from her family. Their analysis revealed that the affected people inherited the genes behind the trait in an autosomal dominant manner.2
Next, together with Fu, the researchers set out to identify the genetic variants responsible for the sleep pattern. They analyzed how people in her family inherited the sleep pattern across generations to map the location of genes underlying the trait. Based on this, they narrowed it down to a missense mutation in the human analog of a gene in fruit flies that is known to alter the circadian period.3 When the researchers engineered mice to carry this variant, the animals showed an advanced sleep-phase pattern.4
Ying-Hui Fu, a human geneticist and sleep scientist at UCSF, studies the genetics of sleep disorders.
Ying-Hui Fu
“When…we told this woman [who approached Jones with her complaint]…that we found the mutation for her and her family, she was so excited,” recalled Fu. After years of uncertainty, she finally understood why she could not stay up late. “She went to all [the] talk shows and essentially did the advertisement for us.”
This publicity soon had a snowball effect: Thousands of people approached the researchers, seeking answers about similar sleep behaviors. Interacting with so many people was enlightening, said Ptáček, because the researchers realized that many of the people reaching out to them were in fact happy with their sleep schedules. “Some of them feel virtuous for being the early bird that gets the worm; others are just indifferent,” said Ptáček. This prompted the research team to rename the tendency as a “trait” rather than the initial labeling of a “syndrome” or “disorder.” Ptáček explained, “It can be considered a disorder, but only when it causes trouble for the subject.”
Over time and by examining more people, the researchers identified more genes and their variants underlying familial advanced sleep-phase trait.5-7 Generating mice with the specific variants helped them better understand the mechanism by which mutations result in distinct phenotypes. Their research revealed that some mutations altered the circadian period such that people’s biological clocks ran shorter than the average 24.2 hours, while some other mutations resulted in people having different sensitivity of resetting their clock to the to the circadian day via light. .
The Challenges and Future of Studying Sleep Genetics
Studies from Drosophila, an important model organism to study the circadian rhythm, have provided vital insights into the molecular mechanisms controlling the biological clock. However, investigating the same mechanisms in people has been difficult.
Fu noted that people live on different schedules compared to model organisms that are kept in fixed environments. Weeding out environmental or artificial cues like lights, meal timings, and exercise, which affect sleep behavior, to better understand human circadian biology is challenging. Despite these obstacles, Fu and Ptáček’s research has revealed important differences between the regulation of the circadian cycle in humans and fruit flies.5
According to Ptáček, understanding the mechanism of circadian control in humans can have immense implications. “All of our biology is linked to our clock,” he said. The circadian rhythm influences the immune system, gastrointestinal health, and drug metabolism among other things, and disrupting the internal clock can cause health issues.8-10
“I’m envisioning medicines, new and better medicines, that might result from understanding the biology that would allow us to do [some] adjustments with our internal clock…that would be so people could fit with their environment, after they travel, when they [work] the night shift,” said Ptáček.
For Fu, the goal is simple. “I want to be able to help everybody get good night’s sleep,” she said.
Voderholzer U, et al. Case report: Treatment of a patient with sleep phase advance disorder with phototherapy. Wien Med Wochenschr. 1995;145(17-18):470-472.Jones CR, et al. Familial advanced sleep-phase syndrome: A short-period circadian rhythm variant in humans. Nat Med. 1999;5(9):1062-1065. Toh KL, et al. An hPer2 phosphorylation site mutation in familial advanced sleep phase syndrome. Science. 2001;291(5506):1040-1043. Xu Y, et al. Modeling of a human circadian mutation yields insights into clock regulation by PER2. Cell. 2007;128(1):59-70. Xu Y, et al. Functional consequences of a CKIδ mutation causing familial advanced sleep phase syndrome. Nature. 2005;434(7033):640-644.Kurien P, et al. TIMELESS mutation alters phase responsiveness and causes advanced sleep phase. Proc Natl Acad Sci USA. 2019;116(24):12045-12053. Webb JM, et al. CACNA1D is a circadian gene and causes familial advanced sleep phase. Proc Natl Acad Sci USA. 2025;122(23):e2424387122. Wang C, et al. The circadian immune system. Sci Immunol. 2022;7(72):eabm2465. Voigt RM, et al. Circadian rhythms: A regulator of gastrointestinal health and dysfunction. Expert Rev Gastroenterol Hepatol. 2019;13(5):411-424. March S, et al. Autonomous circadian rhythms in the human hepatocyte regulate hepatic drug metabolism and inflammatory responses. Sci Adv. 2024;10(17):eadm9281.