Ability to Function on Little Sleep Could Be Genetic

Scientists at the University of California San Francisco have identified a second gene known to promote "natural short sleep", which is defined as lifelong, nightly sleep that lasts just four to six hours yet leaves individuals feeling fully rested.

"Before we identified the first short-sleep gene, people really weren't thinking about sleep duration in genetic terms," said Ying-Hui Fu, Ph.D., who led the research teams that discovered both short sleep genes, the newest of which is described in a paper published today in Neuron.

Natural short sleepers remained a mystery until 2009, when a study conducted by Fu's team discovered that people who had inherited a particular mutation in a gene called DEC2 averaged only 6.25 hours of sleep per night; study participants lacking the mutation averaged 8.06 hours. This finding provided the first conclusive evidence that natural short sleep is, at least in some cases, genetic. But this mutation is rare, so while it helped explain some natural short sleepers, it couldn't account for all of them.

As the new study describes, a breakthrough came when the researchers identified a family that included three successive generations of natural short sleepers, none of whom harbored the DEC2 mutation. The researchers used gene sequencing and linkage analysis to comb through the family's genome. Their efforts uncovered a single-letter mutation in a gene known as ADRB1 that, like the mutation in DEC2, was associated with natural short sleep.

Eager to understand how the newly discovered mutation might lead to short sleep, the researchers performed a series of experiments in lab-grown cells and in a mouse model. The cell-based experiments revealed that the mutant form of the beta-1 adrenergic receptor—the protein encoded by the ADRB1 gene, which plays a role in a variety of essential biological processes—degrades more rapidly than the non-mutant version, suggesting that it might also function differently.

This hunch was confirmed in mouse experiments. The researchers discovered that the ADRB1 gene was highly expressed in the dorsal pons. Using optogenetics, the researchers focused light on neurons in the pons to stimulate those in which ADRB1 was expressed. Triggering these neurons immediately roused sleeping mice—specifically, those that were experiencing non-REM sleep, demonstrating that these neurons promote wakefulness.

Additional experiments showed that wakefulness-promoting neurons in the pons with the mutated version of ADRB1 were more easily activated. Furthermore, the ratio of wakefulness-promoting to sleep-promoting neurons skewed heavily toward the former in mice with the ADRB1 mutation. These experiments suggest that the mutant form of ADRB1 promotes natural short sleep because it helps build brains that are easier to rouse and that stay awake longer.