Mutant Owls
Mutation increased the daily cycle of "owls"
Denis Strigun, Naked Science
A group of scientists from the USA and Turkey found that the delayed onset sleep phase syndrome may be associated with a mutation of the Cry1 gene, which increases the total duration of the sleep-wake cycle.
Delayed sleep phase disorder (DPSD) syndrome manifests itself in a persistent delay in the moment of falling asleep relative to the social norm. According to statistics, up to 10% of people suffer from DPSD, but despite its prevalence, its pathophysiology remains unclear. Meanwhile, it is well known that circadian rhythms are genetically mediated and variations of "clock" transcription factors, for example, the PAS domain (Per-Arnt-Sim), in animals can be obtained by spontaneous or directed mutation. However, in humans, such variations were found only with sleep phase advance syndrome (FASPD): due to a mutation of the Per2 gene, the natural sleep of such patients occurs earlier than normal, for example, at 18-19 hours, and lasts until 3-4 o'clock at night.
To find out what variations are associated with DPSD, employees of Rockefeller University and other institutions examined a 46-year-old American woman (subject TAU11) with this syndrome. Laboratory assessments of twilight melatonin secretion (DLMO), body temperature fluctuations and analysis of motor activity confirmed that the sleep-wake cycle of the subject was increased, amounting to 24.5–24.8 hours. For two days, the growth of melatonin was observed in a woman at about 2:30 versus 20-22 hours in a control participant whose sleep-wake cycle did not exceed 24.2 hours. The authors then sequenced the genes of the volunteers associated with circadian rhythms, additionally comparing the samples of the subject and four relatives.
The scheme of regulation of circadian rhythms by the Cry1 genome. The removal of exon 11 leads to the accumulation of CRY1 cryptochrome in the cell nucleus and enhanced suppression of Clock/Bmal1 (from an article in Cell).
In the course of the work, scientists focused on the genes of the Per and Cry families. They encode cryptochromes that, moving into the cell nucleus, suppress Clock/Bmal1 transcription factors. In the absence of the latter, the expression of cryptochromes stops, and the Clock/Bmal1 complex is reactivated, closing the 24-hour cycle. Sequencing showed that the woman's Cry1 gene contains a specific mutation, in particular, the transversion (replacement) of adenine by cytosine in one of the alleles. As a result of nucleotide replacement, the suppression of the transcription complex is prolonged, increasing the daily cycle. A comparison of samples between relatives also found that the only variation associated with circadian rhythms in family members with DPSD was the mutation mentioned.
In addition, the team studied the sleep-wake cycle of six families from Turkey, 39 members of which were carriers of the variation. This allowed us to determine that, in addition to falling asleep half an hour later than normal or more (due to excessive activity of cryptochrome CRY1), the defect increases the risk of sleep fragmentation and can be inherited from one or both parents. In turn, a search of databases of genetic variants showed that among Europeans, the Cry1 mutation occurs in 0.1–0.6 percent of cases, or in every 75th person. However, she does not explain the phenomenon of "owls" on her own. So, the co-author of the work Alina Patke also attributed herself to people whose activity increases in the evening, although her genome does not contain mutations of this gene.
Article by Patke et al. Mutation of the Human Circadian Clock Gene CRY1 in Familial Delayed Sleep Phase Disorder is published in the journal Cell.
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07.04.2017