Sleep is crucial for our survival, and many conditions, including cancer, autoimmune disorders, cardiovascular disease, and Alzheimer’s, are linked to poor sleep quality. Before we can use sleep to enhance our health and performance and alleviate diseases associated with poor sleep, a greater understanding of sleep regulation is necessary. After a decade of searching, a team of researchers who identified the only gene known to promote natural short sleep — lifelong, nightly sleep that lasts just 4-6 hours yet leaves individuals feeling fully rested — has discovered a second.
A mutation in the ADRB1 gene leads to natural short sleep trait in humans. Image credit: Wok & Apix.
“It’s remarkable that we know so little about sleep, given that the average person spends a third of their lives doing it,” said senior co-author Dr. Louis Ptáček, a neurologist at the University of California, San Francisco.
“This research is an exciting new frontier that allows us to dissect the complexity of circuits in the brain and the different types of neurons that contribute to sleep and wakefulness.”
In 2009, Dr. Ptáček and colleagues discovered that people who had inherited a particular mutation in a gene called DEC2 averaged only 6.25 hours of sleep per night without apparent negative effects. This finding provided the first conclusive evidence that natural short sleep is, at least in some cases, genetic.
“Natural short sleepers experience better sleep quality and sleep efficiency,” said Dr. Ying-Hui Fu, a geneticist at the University of California, San Francisco.
“By studying them, we hope to learn what makes for a good night’s sleep, so that all of us can be better sleepers leading happier, healthier lives.”
In the new study, Dr. Ptáček, Dr. Fu and colleagues uncovered a single-letter mutation in a gene known as ADRB1 that, like the mutation in DEC2, was associated with natural short sleep.
“ADRB1 was identified using genetic linkage studies and whole-exome sequencing, which revealed a novel and very rare variant,” they said.
The first step in deciphering the role of the gene variant involved studying its protein in the test tube.
“We wanted to determine if these mutations caused any functional alterations compared with the wild type,” Dr. Fu explained.
“We found that this gene codes for ß1-adrenergic receptor, and that the mutant version of the protein is much less stable, altering the receptor’s function. This suggested it was likely to have functional consequences in the brain.”
The scientists then conducted a number of experiments in mice carrying a mutated version of the gene.
They found that these mice slept on average 55 minutes less than regular mice; humans with the gene sleep two hours less than average.
Further analysis showed that the ADRB1 gene was expressed at high levels in the dorsal pons, a part of the brain stem involved in subconscious activities such as respiration and eye movement as well as sleep.
Additionally, they discovered that normal ADRB1 neurons in this region were more active not only during wakefulness, but also during rapid eye movement (REM) sleep. However, they were quiet during non-REM sleep.
Furthermore, they found that the mutant neurons were more active than normal neurons, likely contributing to the short sleep behavior.
“Another way we confirmed the role of the protein was using optogenetics. When we used light to activate the ADRB1 neurons, the mice immediately woke up from sleep,” Dr. Fu said.
The study was published in the journal Neuron.
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Guangsen Shi et al. A Rare Mutation of β1-Adrenergic Receptor Affects Sleep/Wake Behaviors. Neuron, published online August 28, 2019; doi: 10.1016/j.neuron.2019.07.026
