Period (gene)

Last updated
per
Identifiers
Organism D. melanogaster
Symbolper
Entrez 31251
RefSeq (mRNA) NM_080317
RefSeq (Prot) NP_525056
UniProt P07663
Other data
Chromosome X: 2.58 - 2.59 Mb
Search for
Structures Swiss-model
Domains InterPro

Period (per) is a gene located on the X chromosome of Drosophila melanogaster . Oscillations in levels of both per transcript and its corresponding protein PER have a period of approximately 24 hours and together play a central role in the molecular mechanism of the Drosophila biological clock driving circadian rhythms in eclosion and locomotor activity. [1] [2] Mutations in the per gene can shorten (perS), lengthen (perL), and even abolish (per0) the period of the circadian rhythm. [1]

Contents

Discovery

The period gene and three mutants (perS, perL, and per0) were isolated in an EMS mutagenesis screen by Ronald Konopka and Seymour Benzer in 1971. [3] The perS, perL, and per0 mutations were found to not complement each other, so it was concluded that the three phenotypes were due to mutations in the same gene. [3] The discovery of mutants that altered the period of circadian rhythms in eclosion and locomotor activity (perS and perL) indicated the role of the per gene in the clock itself and not an output pathway. The period gene was first sequenced in 1984 by Michael Rosbash and colleagues. [4] In 1998, it was discovered that per produces two transcripts (differing only by the alternative splicing of a single untranslated intron) which both encode the PER protein. [5]

Function

Circadian clock

In Drosophila, per mRNA levels oscillate with a period of approximately 24 hours, peaking during the early subjective night. [1] The per product PER also oscillates with a nearly 24-hour period, peaking about six hours after per mRNA levels during the middle subjective night. [6] [ citation needed ] When PER levels increase, the inhibition of per transcription increases, lowering the protein levels. However, because PER protein cannot directly bind to DNA, it does not directly influence its own transcription; alternatively, it inhibits its own activators. [7] After PER is produced from per mRNA, it dimerizes with Timeless (TIM) and the complex goes into the nucleus and inhibits the transcription factors of per and tim, the CLOCK/CYCLE heterodimer. [7] This CLOCK/CYCLE complex acts as a transcriptional activator for per and tim by binding to specific enhancers (called E-boxes) of their promoters. [7] [8] Therefore, inhibition of CLK/CYC lowers per and tim mRNA levels, which in turn lower the levels of PER and TIM. [7] Now, cryptochrome (CRY) is a light sensitive protein which inhibits TIM in the presence of light. [9] When TIM is not complexed with PER, another protein, doubletime, or DBT, phosphorylates PER, targeting it for degradation. [10]

In mammals, an analogous transcription-translation negative feedback loop is observed. [11] Translated from the three mammalian homologs of drosophila-per, one of three PER proteins (PER1, PER2, and PER3) dimerizes via its PAS domain with one of two cryptochrome proteins (CRY1 and CRY2) to form a negative element of the clock. [11] This PER/CRY complex moves into the nucleus upon phosphorylation by CK1-epsilon ( casein kinase 1 epsilon ) and inhibits the CLK/BMAL1 heterodimer, the transcription factor that is bound to the E-boxes of the three per and two cry promoters by basic helix-loop-helix (BHLH) DNA-binding domains. [11]

The mammalian period 1 and period 2 genes play key roles in photoentrainment of the circadian clock to light pulses. [12] [13] This was first seen in 1999 when Akiyama et al. showed that mPer1 is necessary for phase shifts induced by light or glutamate release. [12] Two years later, Albrecht et al. found genetic evidence to support this result when they discovered that mPer1 mutants are not able to advance the clock in response to a late-night light pulse (ZT22) and that mPer2 mutants are not able to delay the clock in response to an early night light pulse (ZT14). [13] Thus, mPer1 and mPer2 are necessary for the daily resetting of the circadian clock to normal environmental light cues. [13]

per has also been implicated in the regulation of several output processes of the biological clock, including mating activity [14] and oxidative stress response, [15] through per mutation and knockout experiments.

Drosophila melanogaster has naturally occurring variation in Thr-Gly repeats, occurring along a latitude cline. Flies with 17 Thr-Gly repeats are found more commonly in Southern Europe and 20 Thr-Gly repeats are found more commonly in Northern Europe. [16]

Non-circadian

In addition to its circadian functions, per has also been implicated in a variety of other non-circadian processes.

The mammalian period 2 gene plays a key role in tumor growth in mice; mice with an mPer2 knockout show a significant increase in tumor development and a significant decrease in apoptosis. [17] This is thought to be caused by mPer2 circadian deregulation of common tumor suppression and cell cycle regulation genes, such as Cyclin D1 , Cyclin A , Mdm-2 , and Gadd45α, as well as the transcription factor c-myc , which is directly controlled by circadian regulators through E box-mediated reactions. [17] In addition, mPer2 knockout mice show increased sensitivity to gamma radiation and tumor development, further implicating mPer2 in cancer development through its regulation of DNA damage-responsive pathways. [17] Thus, circadian control of clock controlled genes that function in cell growth control and DNA damage response may affect the development of cancer in vivo. [17]

per has been shown to be necessary and sufficient for long-term memory (LTM) formation in Drosophila melanogaster . per mutants show deficiencies in LTM formation that can be rescued with the insertion of a per transgene and enhanced with overexpression of the per gene. [18] This response is absent in mutations of other clock genes ( timeless , dClock, and cycle). [18] Research suggests that synaptic transmission through per-expressing cells is necessary for LTM retrieval. [18]

per has also been shown to extend the lifespan of the fruit fly, suggesting a role in aging. [19] This result, however, is still controversial, as the experiments have not been successfully repeated by another research group.

In mice it has been shown that there is a link between per2 and preferred alcohol intake. [20] Alcohol consumption has also been linked to shortening the free running period. [21] The effect of alcoholism on per1 and per2 genes have also linked to the depression associated with alcohol as well as an individual's disposition to relapse into alcoholism. [21]

Mammalian homologs of per

In mammals, there are three known PER family genes: PER1, PER2, and PER3. The mammalian molecular clock has homologs to the proteins found in Drosophila. A homolog of CLOCK plays the same role in the human clock, and CYC is replaced by BMAL1. [7] CRY has two human homologs, CRY1 and CRY2, which was discovered by Edmund A. Griffin, Jr., David Staknis and Charles J. Weitz to encompass light-independent interactions with CLOCK and BMAL1. [22] A computational model for model has been developed by Jean-Christophe Leloup and Albert Goldbeter to simulate the feedback loop created by the interactions between these proteins and genes, including the per gene and PER protein. [23]

period homolog 1 (Drosophila)
Identifiers
Symbol PER1
NCBI gene 5187
HGNC 8845
OMIM 602260
RefSeq NM_002616
UniProt O15534
Other data
Locus Chr. 17 p12
Search for
Structures Swiss-model
Domains InterPro
period homolog 2 (Drosophila)
Identifiers
Symbol PER2
NCBI gene 8864
HGNC 8846
OMIM 603426
RefSeq NM_003894
UniProt O15055
Other data
Locus Chr. 2 q37.3
Search for
Structures Swiss-model
Domains InterPro
period homolog 3 (Drosophila)
Identifiers
Symbol PER3
NCBI gene 8863
HGNC 8847
OMIM 603427
RefSeq NM_016831
UniProt P56645
Other data
Locus Chr. 1 p36.23
Search for
Structures Swiss-model
Domains InterPro

The human homologs show sequence and amino acid similarity to Drosophila Per and also contain the PAS domain and nuclear localization sequences that the Drosophila Per have. The human proteins are expressed rhythmically in the suprachiasmatic nucleus as well as areas outside the SCN. Additionally, while Drosophila PER moves between the cytoplasm and the nucleus, mammalian PER is more compartmentalized: mPer1 primarily localizes to the nucleus and mPer2 to the cytoplasm. [24]

Clinical significance

Familial advanced sleep-phase syndrome known to be associated with mutations in the mammalian Per2 gene. People suffering from the disorder have a shorter period and advanced phase where they go to sleep in the early evening (around 7pm) and wake up before sunrise (around 4am). In 2006, a lab in Germany identified particular phosphorylated residues of PER2 that are mutated in people suffering of FASPS. [25] Chronotherapy is sometimes used as a treatment, as an attempt to alter the phase of the individual's clock using cycles of bright light.

See also

Related Research Articles

<span class="mw-page-title-main">Cryptochrome</span> Class of photoreceptors in plants and animals

Cryptochromes are a class of flavoproteins found in plants and animals that are sensitive to blue light. They are involved in the circadian rhythms and the sensing of magnetic fields in a number of species. The name cryptochrome was proposed as a portmanteau combining the chromatic nature of the photoreceptor, and the cryptogamic organisms on which many blue-light studies were carried out.

The Casein kinase 1 family of protein kinases are serine/threonine-selective enzymes that function as regulators of signal transduction pathways in most eukaryotic cell types. CK1 isoforms are involved in Wnt signaling, circadian rhythms, nucleo-cytoplasmic shuttling of transcription factors, DNA repair, and DNA transcription.

<span class="mw-page-title-main">CLOCK</span> Human protein and coding gene

CLOCK is a gene encoding a basic helix-loop-helix-PAS transcription factor that is known to affect both the persistence and period of circadian rhythms.

Timeless (tim) is a gene in multiple species but is most notable for its role in Drosophila for encoding TIM, an essential protein that regulates circadian rhythm. Timeless mRNA and protein oscillate rhythmically with time as part of a transcription-translation negative feedback loop involving the period (per) gene and its protein.

<span class="mw-page-title-main">PER3</span> Protein and coding gene in humans

The PER3 gene encodes the period circadian protein homolog 3 protein in humans. PER3 is a paralog to the PER1 and PER2 genes. It is a circadian gene associated with delayed sleep phase syndrome in humans.

<span class="mw-page-title-main">PER2</span> Protein-coding gene in the species Homo sapiens

PER2 is a protein in mammals encoded by the PER2 gene. PER2 is noted for its major role in circadian rhythms.

<span class="mw-page-title-main">Period circadian protein homolog 1</span> Protein-coding gene in the species Homo sapiens

Period circadian protein homolog 1 is a protein in humans that is encoded by the PER1 gene.

In molecular biology, an oscillating gene is a gene that is expressed in a rhythmic pattern or in periodic cycles. Oscillating genes are usually circadian and can be identified by periodic changes in the state of an organism. Circadian rhythms, controlled by oscillating genes, have a period of approximately 24 hours. For example, plant leaves opening and closing at different times of the day or the sleep-wake schedule of animals can all include circadian rhythms. Other periods are also possible, such as 29.5 days resulting from circalunar rhythms or 12.4 hours resulting from circatidal rhythms. Oscillating genes include both core clock component genes and output genes. A core clock component gene is a gene necessary for to the pacemaker. However, an output oscillating gene, such as the AVP gene, is rhythmic but not necessary to the pacemaker.

Pigment dispersing factor (pdf) is a gene that encodes the protein PDF, which is part of a large family of neuropeptides. Its hormonal product, pigment dispersing hormone (PDH), was named for the diurnal pigment movement effect it has in crustacean retinal cells upon its initial discovery in the central nervous system of arthropods. The movement and aggregation of pigments in retina cells and extra-retinal cells is hypothesized to be under a split hormonal control mechanism. One hormonal set is responsible for concentrating chromatophoral pigment by responding to changes in the organism's exposure time to darkness. Another hormonal set is responsible for dispersion and responds to the light cycle. However, insect pdf genes do not function in such pigment migration since they lack the chromatophore.

<i>Cycle</i> (gene)

Cycle (cyc) is a gene in Drosophila melanogaster that encodes the CYCLE protein (CYC). The Cycle gene (cyc) is expressed in a variety of cell types in a circadian manner. It is involved in controlling both the sleep-wake cycle and circadian regulation of gene expression by promoting transcription in a negative feedback mechanism. The cyc gene is located on the left arm of chromosome 3 and codes for a transcription factor containing a basic helix-loop-helix (bHLH) domain and a PAS domain. The 2.17 kb cyc gene is divided into 5 coding exons totaling 1,625 base pairs which code for 413 aminos acid residues. Currently 19 alleles are known for cyc. Orthologs performing the same function in other species include ARNTL and ARNTL2.

Doubletime (DBT), also known as discs overgrown (DCO), is a gene that encodes the double-time protein in fruit flies. The gene was first identified and characterized in 1998 by Michael Young and his team at Rockefeller University.

<span class="mw-page-title-main">Michael Rosbash</span> American geneticist and chronobiologist (born 1944)

Michael Morris Rosbash is an American geneticist and chronobiologist. Rosbash is a professor and researcher at Brandeis University and investigator at the Howard Hughes Medical Institute. Rosbash's research group cloned the Drosophila period gene in 1984 and proposed the Transcription Translation Negative Feedback Loop for circadian clocks in 1990. In 1998, they discovered the cycle gene, clock gene, and cryptochrome photoreceptor in Drosophila through the use of forward genetics, by first identifying the phenotype of a mutant and then determining the genetics behind the mutation. Rosbash was elected to the National Academy of Sciences in 2003. Along with Michael W. Young and Jeffrey C. Hall, he was awarded the 2017 Nobel Prize in Physiology or Medicine "for their discoveries of molecular mechanisms controlling the circadian rhythm".

<span class="mw-page-title-main">Casein kinase 1 isoform epsilon</span> Protein and coding gene in humans

Casein kinase I isoform epsilon or CK1ε, is an enzyme that is encoded by the CSNK1E gene in humans. It is the mammalian homolog of doubletime. CK1ε is a serine/threonine protein kinase and is very highly conserved; therefore, this kinase is very similar to other members of the casein kinase 1 family, of which there are seven mammalian isoforms. CK1ε is most similar to CK1δ in structure and function as the two enzymes maintain a high sequence similarity on their regulatory C-terminal and catalytic domains. This gene is a major component of the mammalian oscillator which controls cellular circadian rhythms. CK1ε has also been implicated in modulating various human health issues such as cancer, neurodegenerative diseases, and diabetes.

Hitoshi Okamura is a Japanese scientist who specializes in chronobiology. He is currently a professor of Systems Biology at Kyoto University Graduate School of Pharmaceutical Sciences and the Research Director of the Japan Science Technology Institute, CREST. Okamura's research group cloned mammalian Period genes, visualized clock oscillation at the single cell level in the central clock of the SCN, and proposed a time-signal neuronal pathway to the adrenal gland. He received a Medal of Honor with Purple Ribbon in 2007 for his research and was awarded Aschoff's Ruler for his work on circadian rhythms in rodents. His lab recently revealed the effects of m6A mRNA methylation on the circadian clock, neuronal communications in jet lag, and the role of dysregulated clocks in salt-induced hypertension.

Paul Hardin is an American scientist in the field of chronobiology and a pioneering researcher in the understanding of circadian clocks in flies and mammals. Hardin currently serves as a distinguished professor in the biology department at Texas A&M University. He is best known for his discovery of circadian oscillations in the mRNA of the clock gene Period (per), the importance of the E-Box in per activation, the interlocked feedback loops that control rhythms in activator gene transcription, and the circadian regulation of olfaction in Drosophila melanogaster. Born in a suburb of Chicago, Matteson, Illinois, Hardin currently resides in College Station, Texas, with his wife and three children.

<i>Drosophila</i> circadian rhythm

Drosophila circadian rhythm is a daily 24-hour cycle of rest and activity in the fruit flies of the genus Drosophila. The biological process was discovered and is best understood in the species Drosophila melanogaster. Other than normal sleep-wake activity, D. melanogaster has two unique daily behaviours, namely regular vibration during the process of hatching from the pupa, and during mating. Locomotor activity is maximum at dawn and dusk, while eclosion is at dawn.

Transcription-translation feedback loop (TTFL) is a cellular model for explaining circadian rhythms in behavior and physiology. Widely conserved across species, the TTFL is auto-regulatory, in which transcription of clock genes is regulated by their own protein products.

Hajime Tei is a Japanese neuroscientist specializing in the study of chronobiology. He currently serves as a professor at the Kanazawa University Graduate School of Natural Science & Technology. He is most notable for his contributions to the discovery of the mammalian period genes, which he discovered alongside Yoshiyuki Sakaki and Hitoshi Okamura.

dClock (clk) is a gene located on the 3L chromosome of Drosophila melanogaster. Mapping and cloning of the gene indicates that it is the Drosophila homolog of the mouse gene CLOCK (mClock). The Jrk mutation disrupts the transcription cycling of per and tim and manifests dominant effects.

Charles J. Weitz is a chronobiologist and neurobiologist whose work primarily focuses on studying the molecular biology and genetics of circadian clocks.

References

  1. 1 2 3 Hardin PE, Hall JC, Rosbash M (February 1990). "Feedback of the Drosophila period gene product on circadian cycling of its messenger RNA levels". Nature. 343 (6258): 536–40. Bibcode:1990Natur.343..536H. doi:10.1038/343536a0. PMID   2105471. S2CID   4311836.
  2. ↑ Dunlap, JC (January 1999). "Molecular Bases for Circadian Clocks". Cell. 96 (2): 271–290. doi: 10.1016/S0092-8674(00)80566-8 . PMID   9988221. S2CID   14991100.
  3. 1 2 Konopka RJ, Benzer S (September 1971). "Clock mutants of Drosophila melanogaster". Proc. Natl. Acad. Sci. U.S.A. 68 (9): 2112–6. Bibcode:1971PNAS...68.2112K. doi: 10.1073/pnas.68.9.2112 . PMC   389363 . PMID   5002428.
  4. ↑ Reddy P, Zehring WA, Wheeler DA, Pirrotta V, Hadfield C, Hall JC, Rosbash M (October 1984). "Molecular analysis of the period locus in Drosophila melanogaster and identification of a transcript involved in biological rhythms". Cell. 38 (3): 701–10. doi:10.1016/0092-8674(84)90265-4. PMID   6435882. S2CID   316424.
  5. ↑ Cheng Y, Gvakharia B, Hardin PE (November 1998). "Two Alternatively Spliced Transcripts from the Drosophila period Gene Rescue Rhythms Having Different Molecular and Behavioral Characteristics". Molecular and Cellular Biology. 18 (11): 6505–6514. doi:10.1128/MCB.18.11.6505. PMC   109236 . PMID   9774666.
  6. ↑ Siwicki KK, Eastman C, Peterson G, Rosbash M, Hall JC (April 1988). "Antibodies to the period Gene Product of Drosophila Reveal Diverse Tissue Distribution and Rhythmic Changes in the Visual System". Neuron. 1 (2): 141–150. doi:10.1016/0896-6273(88)90198-5. PMID   3152288. S2CID   18926915.
  7. 1 2 3 4 5 Ishida N, Kaneko M, Allada R (August 1999). "Biological clocks". Proc. Natl. Acad. Sci. U.S.A. 96 (16): 8819–20. Bibcode:1999PNAS...96.8819I. doi: 10.1073/pnas.96.16.8819 . PMC   33693 . PMID   10430850.
  8. ↑ Hao H, Allen DL, Hardin PE (July 1997). "A circadian enhancer mediates PER-dependent mRNA cycling in Drosophila melanogaster". Molecular and Cellular Biology. 17 (7): 3687–3693. doi:10.1128/MCB.17.7.3687. PMC   232220 . PMID   9199302.
  9. ↑ Ceriani MF, Darlington TK, Staknis D, Más P, Petti AA, Weitz CJ, Kay SA (July 1999). "Light-dependent sequestration of TIMELESS by CRYPTOCHROME". Science. 285 (5427): 553–6. doi:10.1126/science.285.5427.553. PMID   10417378.
  10. ↑ Kivimäe S, Saez L, Young MW (July 2008). "Activating PER repressor through a DBT-directed phosphorylation switch". PLOS Biology. 6 (7): e183. doi: 10.1371/journal.pbio.0060183 . PMC   2486307 . PMID   18666831.
  11. 1 2 3 Ko CH, Takahashi JS (July 2006). "Molecular components of the mammalian circadian clock". Human Molecular Genetics. 15 (2): 271–277. doi: 10.1093/hmg/ddl207 . PMC   3762864 . PMID   16987893.
  12. 1 2 Akiyama M, Kouzu Y, Takahashi S, Wakamatsu H, Moriya T, Maetani M, Watanabe S, Tei H, Sakaki Y, Shibata S (February 1999). "Inhibition of light- or glutamate-induced mPer1 expression represses the phase shifts into the mouse circadian locomotor and suprachiasmatic firing rhythms". J. Neurosci. 19 (3): 1115–21. doi:10.1523/JNEUROSCI.19-03-01115.1999. PMC   6782139 . PMID   9920673.
  13. 1 2 3 Albrecht U, Zheng B, Larkin D, Sun ZS, Lee CC (April 2001). "MPer1 and mper2 are essential for normal resetting of the circadian clock". J. Biol. Rhythms. 16 (2): 100–4. doi: 10.1177/074873001129001791 . PMID   11302552. S2CID   9067400.
  14. ↑ Sakai T, Ishida N (July 2001). "Circadian rhythms of female mating activity governed by clock genes in Drosophila". Proc. Natl. Acad. Sci. U.S.A. 98 (16): 9221–5. Bibcode:2001PNAS...98.9221S. doi: 10.1073/pnas.151443298 . PMC   55401 . PMID   11470898.
  15. ↑ Krishnan N, Davis AJ, Giebultowicz JM (September 2008). "Circadian regulation of response to oxidative stress in Drosophila melanogaster". Biochem. Biophys. Res. Commun. 374 (2): 299–303. doi:10.1016/j.bbrc.2008.07.011. PMC   2553425 . PMID   18627767.
  16. ↑ Costa R, Peixoto AA, Barbujani G, Kyriacou CP (October 1992). "A latitudinal cline in a Drosophila clock gene". Proc. Biol. Sci. 250 (1327): 43–49. Bibcode:1992RSPSB.250...43C. doi:10.1098/rspb.1992.0128. PMID   1361061. S2CID   8441173.
  17. 1 2 3 4 Fu L, Pelicano H, Liu J, Huang P, Lee C (October 2002). "The circadian gene Period2 plays an important role in tumor suppression and DNA damage response in vivo". Cell. 111 (1): 41–50. doi: 10.1016/S0092-8674(02)00961-3 . PMID   12372299. S2CID   968337.
  18. 1 2 3 Sakai T, Tamura T, Kitamoto T, Kidokoro Y (November 2004). "A clock gene, period, plays a key role in long-term memory formation in Drosophila". Proc. Natl. Acad. Sci. U.S.A. 101 (45): 16058–63. Bibcode:2004PNAS..10116058S. doi: 10.1073/pnas.0401472101 . PMC   528738 . PMID   15522971.
  19. ↑ Krishnan N, Kretzschmar D, Rakshit K, Chow E, Giebultowicz JM (November 2009). "The circadian clock gene period extends healthspan in aging Drosophila melanogaster". Aging. 1 (11): 937–48. doi:10.18632/aging.100103. PMC   2815745 . PMID   20157575.
  20. ↑ Spanagel R, Pendyala G, Abarca C, Zghoul T, Sanchis-Segura C, Magnone MC, Lascorz J, Depner M, Holzberg D, Soyka M, Schreiber S, Matsuda F, Lathrop M, Schumann G, Albrecht U (January 2005). "The clock gene Per2 influences the glutamatergic system and modulates alcohol consumption" (PDF). Nat. Med. 11 (1): 35–42. doi:10.1038/nm1163. PMID   15608650. S2CID   11106714.
  21. 1 2 Spanagel R, Rosenwasser AM, Schumann G, Sarkar DK (August 2005). "Alcohol consumption and the body's biological clock". Alcohol. Clin. Exp. Res. 29 (8): 1550–7. doi:10.1097/01.alc.0000175074.70807.fd. PMID   16156052.
  22. ↑ Griffin EA, Staknis D, Weitz CJ (October 1999). "Light-independent role of CRY1 and CRY2 in the mammalian circadian clock". Science. 286 (5440): 768–71. doi:10.1126/science.286.5440.768. PMID   10531061.
  23. ↑ Leloup JC, Goldbeter A (June 2003). "Toward a detailed computational model for the mammalian circadian clock". Proc. Natl. Acad. Sci. U.S.A. 100 (12): 7051–6. Bibcode:2003PNAS..100.7051L. doi: 10.1073/pnas.1132112100 . PMC   165828 . PMID   12775757.
  24. ↑ Vielhaber E, Eide E, Rivers A, Gao ZH, Virshup DM (July 2000). "Nuclear entry of the circadian regulator mPER1 is controlled by mammalian casein kinase I epsilon". Molecular Cell Biology. 20 (13): 4888–99. doi:10.1128/MCB.20.13.4888-4899.2000. PMC   85940 . PMID   10848614.
  25. ↑ Vanselow K, Vanselow JT, Westermark PO, Reischl S, Maier B, Korte T, Herrmann A, Herzel H, Schlosser A, Kramer A (October 2006). "Differential effects of PER2 phosphorylation: molecular basis for the human familial advanced sleep phase syndrome (FASPS)". Genes Dev. 20 (19): 2660–72. doi:10.1101/gad.397006. PMC   1578693 . PMID   16983144.
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