Egad! Why will the girl not sleep?

I'm not a very good sleeper.  Ask my parents.  They'll tell you stories of me at age 3 or so wandering the house in the wee hours of the morning, because I was just awake.  And I recall many nights, even now, where it will take me 2 hours to fall asleep.  And naps?  Unless I'm so sleepy I'm stumbling, forget about it.  In college they called me the "sleep camel" because I would sleep 5-6 hours per night for a few weeks then spend one entire weekend in bed, catching up.  We all have our own sleep patterns that are unique to us, and very few of us fit the average 8-9 hours per night, 10 pm to 6 am kind of pattern.  So it didn't surprise me when my first daughter exhibited similar sleep patterns to me.  After all, she has my nose, my eyebrows, my smile, why not my sleep habits too?  It got me thinking if there was a genetic basis to sleep behaviors.  And guess what, the answer is absolutely! 

Sleep patterns, or more broadly, circadian rhythms, can be thought of as how we live around that 24 hour day/night cycle.  It is well appreciated that circadian rhythms influence nearly every biological process in our bodies: metabolism, cell cycle, tissue repair, digestion, gene transcription, you name it.  So it should come as no surprise that a complex network of genes and proteins dedicated to keeping us in-sync with the sun. A quick search of the Gene Ontology database for "Circadian Rhythm" produced 487 distinct protein products associated with the day/night cycle. 

The genetic basis of sleep patterns are most easily thought of as complex traits: many genes are involved, and the equation is muddled by environment.  For example, our sleep patterns as a society changed drastically with the advent of electricity.  So how can we separate out what component of sleep behavior is genetic and what is environment, or learned behavior?  One easy way is to look at extreme examples where researchers have identified unusual patterns running in families and performed exhaustive searches to identify single genes associated with those behaviors.  While mutations in these genes are exceedingly rare, one can imagine how subtle differences in these genes, or others yet to be discovered, can contribute to a sort of "genetic sleep fingerprint" that is common in a family.

"Early Bird Gene".

The disorder known as familial advanced sleep phase syndrome (FASPS) is a rare, inherited disorder characterized with early rising.  Individuals typically wake at 4 AM, and go to sleep at an early time as well, about 7 PM.  While this disorder is considered non pathogenic, individuals are normal and healthy, it does cause some psychological difficulties as patients feel "out of step" with the rest of society.

In 2005, researchers at UCSF studied a family with three generations of FASPS sufferers, and identified a gene, CKI delta, or hPeriod2, associated with the early sleep, early rise phenotype (Xu et al, 2005). They reported in 2007 that mice carrying two mutated copies of the mutated Period2 gene exhibit similar shifts in sleep patterns (Cy et al, 2007 and Zheng et al, 1999).  The mice had changes to their metabolism, their hormones (estrogen levels were altered), neurotransmitter levels, and alcohol consumption. Talk about broad effects.  

"Short Sleeper Gene"
Another rare reported sleep phenotype reported in families is that of short sleep duration.  These individuals typically sleep only 6.5 hours or so per night, rather than the 8-9 hours more typical of humans.  The trait was mapped to the gene DEC2 (He et al, 2009).  The gene DEC2 codes for a transcription factor, a protein that controls the expression of other genes.  DEC2, and a related gene DEC1, are found to regulate expression of other circadian rhythm genes such as Clock/BMAL1 and PER1 by hooking onto their promoters, little DNA bits upstream of the gene, and turning on expression (Honama et al, 2002).  And, at least in the case of DEC1, gene expression is regulated by light exposure. 

Transgenic mice that have both copies of their mouse-version of DEC2 gene mutated are more active and sleep less than mice with the normal, functional gene.  But mice that have both copies deleted do not exhibit this phenotype, suggesting the mutation seen in these mice (and by extension in humans) is a functional variant, retaining some activity but altered in either specificity or regulation.

"Night Owl Gene"

And rounding out our sleep gene sampling is a gene that when mutated results in people staying up late.  Well, it's not really been shown in people yet, but in mice, mutations in the gene Fbxl3 resulted in the mice having an "overtime" phenotype, where their circadian rhythm was pushed from 24 to about 27 hours (Siepka et al, 2007).  This gene encodes an f-box protein - a protein involved in the ubquitin ligase/proteasomal  degradation pathway. So, Fbxl3 tags proteins to be degraded and recycled.  Work coming from the Pagano lab showed that the circadian rhythm protein Cry2 was ubiquitinated by Fbxl3, and this results in the protein Clock to be reactivated (Busino et al, 2007).  So, Fbxl3 plays a key role in the timekeeping mechanism in a cell, and without it, well, cells, and mice, don't follow the sun.

This is just a teeny, isty-bitsy sampling of some interesting genes involved in keeping us awake in the day and sleeping at night.  I keep these genes, and the 484 more identified in the circadian rhythm pathway, in mind when my 2 1/2 year old decides that 10.5 hours of sleep per day is sufficient for her, and that 5:30 AM is a perfectly reasonable time to wake. She, like me and her dad and everyone else, was born with her own sleep patterns. I do try to coax her into that extra half-hour in the morning, but I know that as long as I provide the right opportunity and conditions for her, she will get the sleep that she needs.  Maybe she's a sleep camel too. 

REFERENCES:

Busino, L., Bassermann, F., Maiolica, A., Lee, C., Nolan, P. M., Godinho, S. I. H., Draetta, G. F., Pagano, M. SCF-Fbxl3 controls the oscillation of the circadian clock by directing the degradation of cryptochrome proteins. Science 316: 900-904, 2007

He, Y., Jones, C. R., Fujiki, N., Xu, Y., Guo, B., Holder, J. L., Jr., Rossner, M. J., Nishino, S., Fu, Y.-H. The transcriptional repressor DEC2 regulates sleep length in mammals. Science 325: 866-870, 2009.

Honma, S., Kawamoto, T., Takagi, Y., Fujimoto, K., Sato, F., Noshiro, M., Kato, Y., Honma, K. Dec1 and Dec2 are regulators of the mammalian molecular clock. Nature 419: 841-844, 2002. 

Siepka, S. M., Yoo, S.-H., Park, J., Song, W., Kumar, V., Hu, Y., Lee, C., Takahashi, J. S. Circadian mutant Overtime reveals F-box protein FBXL3 regulation of Cryptochrome and Period gene expression. Cell129: 1011-1023, 2007.

Xu Y, Padiath QS, Shapiro RE, Jones CR, Wu SC, Saigoh N, Saigoh K, Ptácek LJ, Fu YH .Functional consequences of a CKIdelta mutation causing familial advanced sleep phase syndrome.   Nature. 2005 Mar 31;434(7033):640-4.Xu Y, Toh KL, Jones CR, Shin JY, Fu YH, Ptácek LJ. Modeling of a human circadian mutation yields insights into clock regulation by PER2.

Cell. 2007 Jan 12;128(1):59-70.

Zheng, B., Larkin, D. W., Albrecht, U., Sun, Z. S., Sage, M., Eichele, G., Lee, C. C., Bradley, A. The mPer2 gene encodes a functional component of the mammalian circadian clock. Nature 400: 169-173, 1999.