Waking up to the mechanisms of sleep

Researchers identify genetic mutations that influence sleep.

Sleep is ubiquitous across the animal kingdom yet little is known about the mechanisms that regulate it. A new Nature study has identified two genetic mutations that influence the type and amount of sleep experienced by mice. Hiromasa Funato, University of Tsukuba, and colleagues made this discovery by examining the sleep patterns of more than 8,000 mice with randomly generated genetic mutations.

Sleep has two different states; non-rapid-eye-movement sleep (NREM sleep or deep sleep) and rapid-eye-movement sleep (REM sleep or dream sleep). The first mutation identified in the study, which affected the Sik3gene, increased the amount of NREM sleep. This means that the total time spent awake was reduced and the inherent need for sleep was increased.

The second mutation affected the Nalcn gene and reduced the total amount and length of REM sleep. The authors believe this to be a result of the REM-sleep-inhibiting neurons becoming more excitable.

We spoke to Funato about the study.

ResearchGate: Why do we know so little about sleep?

Hiromasa Funato: I believe that an epoch-making discovery is necessary to open a new field. One good examples was the discovery of leptin, which enabled us to approach obesity in a scientific way.

I don’t think there has been an equivalent discovery in sleep research. We hope our discovery will change that.

RG: What have you discovered? How do these genes regulate slumber?

Funato: We found two gene mutations. One mutation in the Sik3gene, which drastically decreased time spent in wakefulness. Mice with the mutation in the Nalcn gene showed very short REM sleep.

We are now working out how Sik3 and Nalcn regulate sleep. I hope we will be able to answer your second question in the near future.

RG: How did you discover this?

Funato: We examined 8,000 mutagenized mice for sleep abnormality. These mice had a lot of random mutations which were induced using ethyl nitrosourea.

One day, we found several mice showing long sleep so we crossed them with female mice to obtain the next generation. It turned out that the offspring also showed long sleep like their fathers, which means that we successfully established a family of long sleeper mice.

We then conducted linkage analysis to figure out which part of chromosomes is associated with long sleep and performed whole exome sequencing to find gene mutations.

Combining the results from linkage analysis and whole exome sequencing, we identified a single mutation in the Sik3 gene.

RG: Can you tell us what this means for our understanding of sleep?

Funato: One implication is that your genes may determine how many hours you need to sleep. There are likely unknown genetic differences between long sleepers and short sleepers

RG: How does mouse sleep differ to human sleep?

Funato: There are two big differences between mouse and human sleep: Mouse sleep is polyphasic whereas human sleep is monophasic. Mice are nocturnal and humans are usually diurnal. But overall, mouse sleep is very similar to human sleep.

RG: What does the study tell you about human sleep?

Funato: Humans also have the Sik3 and Nalcn genes, and we believe they are also involved in human sleep.

RG: What potential applications does this discovery have?

Funato: We hope that this eventually leads to the development of a new class of sleeping pill.

RG: What’s next?

Funato: We are just beginning to open up the mystery of sleep. There is a long way to go.

We would like to continue our current project to discover other genes that regulate sleep. Eventually, we can connect these genes and get an overall picture of how sleep is regulated.

Featured image courtesy of Dean Hochman.