A New Gene Helps Explain Why Some People Need Less Sleep

In 2009, Ying-Hui Fu started getting a flood of emails from people who claimed to only need a few hours of sleep at night. Fu and her colleague and spouse Louis Ptáček, both at the University of California, San Francisco, had just identified a gene mutation that significantly decreased how many hours someone needs to sleep. It was the first such gene discovered. Now, it seemed, the entirety of the short-sleeping universe was deluging her inbox.

One man described how he only slept about five and a half hours each night. His son slept a bit more than four. But the two were happy, energetic, and healthy. They weren’t cranky or forgetful like most sleep-deprived people would be. Fu’s lab interviewed the pair, enrolled them in a study, and took samples of their blood.

Using those samples, Fu and Ptáček have now identified a new gene mutation associated with short sleepers, which they describe in a paper out today in Science Translational Medicine. The mutation is helping scientists understand how our bodies regulate sleep. It’s only the third short-sleep mutation found so far, though Fu and other scientists suspect there are several more. “We don’t know how these different genes converge together to regulate sleep,” says Fu. But each new gene discovery helps elucidate how these interrelated pathways control our 40 winks.

Sleep is fundamental to human life. It reduces anxiety and inflammation, improves cognitive functions like memory, attention, and alertness, and helps regulate mood. People who are chronically sleep deprived have a higher risk of diabetes, cancer, and Alzheimer’s disease. But scientists understand little about how our bodies control this all-important function.

Short sleepers are a rarity. While most people need around eight hours of sleep to be in tip-top shape, short sleepers need only between four and six hours to function just as well. They don’t need naps or long weekend snoozes to catch up. In one month they might collect 75 more awake hours than their well-rested, more typical counterparts. Imagine the amount of Netflix binge watching, email answering, marathon training, or book reading a person could do.

David Dinges, a psychiatrist who studies sleep at the University of Pennsylvania and who was not involved in the study, says that just identifying true genetic short-sleepers, like the father-son duo, is a victory. But Fu’s paper does even more. “There is an ability to identify what the mechanism might be in the brain, that’s still pretty novel in the sleep field,” he says.

Fu looks for sleep-related mutations because those extremes help bring the whole system into relief. But searching for a single gene is challenging. That’s why having a father-son pair was so helpful. The research team limited their focus to genes the two had in common. Eventually they found a single letter mutation in the NPSR1 gene, which codes for a particular neuron receptor. Earlier research had shown that activating that receptor helps keep people awake.

Next they bred mice with the mutation and examined their sleep patterns. The mutated mice did sleep for shorter periods, but the reduction wasn’t as dramatic as it is in the father-and-son team who inspired their creation. That may be because mice have different sleep habits than humans—dozing off at multiple intervals during a 24-hour period, for shorter stretches of time—or because more than one gene is involved in regulating this aspect of sleep.

More revealing, perhaps, is the fact that the mice also behaved normally, just like the father and son. In particular, their memory appeared intact. To test this, the researchers subjected the mice to random electric shocks in a certain room. Typically, sleep-deprived mice won’t remember the shocks the next day and will walk blithely across the room. But when the mutant mice were placed in the same room, they did remember and moved hesitantly.

“I didn’t expect that a mutation in the receptor would be so dramatic in humans,” says Luis de Lecea, a biologist at Stanford who first identified the receptor in 2004. His work showed that the receptor plays a role in anxiety and increased wakefulness, so he isn’t surprised to see that it might be involved in sleep regulation too. But he says this gene discovery isn’t the key to the whole sleep mystery. “It’s just one system that contributes to sleep modulation,” he says. “And it may be an important one. But we don’t know yet.”

Fu suspects this mutation helps people sleep more efficiently. If you think of the body as a machine, sleep is the after-hours maintenance. Cerebrospinal fluid washes over the brain during sleep, cleaning out waste products like beta-amyloid, a toxic protein linked to Alzheimer’s that is created by normal brain activity. People with the mutation appear to be doing that cleaning much more efficiently.

The mutation is rare; only one in 4 million people has it. But understanding how that pathway works could help everyone. For insomniacs or people who can’t get enough sleep, it could help researchers eventually develop medications that help them maximize the benefits of the little sleep they can get.

Fu is trying to identify more genes as quickly as she can so other researchers can get to work figuring out all of these questions. “For me, it’s more interesting to help everybody sleep better,” she says. She wants to turn her attention to long sleepers, people who tend to need around 10 to 12 hours a night, and hopes they will reach out after this study publishes. With any luck, a lead on a new gene discovery will be waiting in her inbox.