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Not medical advice. The Atlas is not a substitute for a clinician who can examine you.

Clock Genes

CLOCK, BMAL1, PER, CRY · The Molecular Clock

Evidence grade 5 of 5, Settled. Read how the Atlas grades evidence.

0 human trials, about 2000 studies, 2017 participants Nobel Prize in Physiology or Medicine. The written rationale for this grade is still being prepared.

FDA
Foundational biology
WADA
Not prohibited

Reference only. Not medical advice.

What can go wrong

This entry is mechanism, not a protocol. Clock-gene variants (PER3, CLOCK, CRY1) are associated with chronotype and with some inherited sleep-timing disorders, useful background, but direct-to-consumer chronotype gene tests often imply more actionable precision than the science supports. Persistent or distressing sleep-timing problems, especially when sleep is significantly out of step with school, work, or daily life, warrant evaluation by a qualified sleep medicine or healthcare provider rather than a mail-in genetic kit. Pediatric and adolescent sleep concerns in particular should be directed to a qualified provider.

The molecular clock is a transcription-translation feedback loop that runs in nearly every cell, not only in the brain. The CLOCK:BMAL1 protein complex switches on the Period (PER) and Cryptochrome (CRY) genes; the PER and CRY proteins build up, pair off, re-enter the nucleus, and shut down their own transcription, a cycle that takes about 24 hours. A second, stabilizing loop built on the nuclear receptors REV-ERB and ROR tunes BMAL1 and ties the clock to metabolism. The architecture was decoded over five decades, from fruit-fly mutants in 1971 to the mouse Clock gene in the 1990s. Jeffrey Hall, Michael Rosbash, and Michael Young received the 2017 Nobel Prize in Physiology or Medicine for the work.

The 24-hour feedback loop inside every cell. The 2017 Nobel Prize in Medicine.

What people take it for

What it is taken for. Approval, where it exists, covers only some of these.

  • Explaining why nearly every tissue keeps its own ~24-hour time
  • Framework for chronotype genetics and morningness-eveningness
  • Foundation for chronopharmacology and time-of-day drug dosing research
  • Basis for understanding inherited sleep-timing differences such as familial delayed sleep phase disorder
  • Reference point for evaluating what direct-to-consumer chronotype gene tests can and cannot deliver

What people get wrong

  • Often saidClock genes are only in the brain

    ActuallyThe same transcription-translation feedback loop runs in nearly every cell, liver, muscle, fat, gut, which is why the timing of meals and movement signals the body broadly, not just sleep. The central pacemaker in the brain coordinates these peripheral clocks rather than housing the clock alone (King et al., Cell 1997; Nobel 2017 advanced information).

  • Often saidThe clock is a single gene

    ActuallyIt is a network. The positive arm is CLOCK:BMAL1; the negative arm is PER:CRY; a second stabilizing loop runs through the nuclear receptors REV-ERB and ROR. Drosophila genetics named period, timeless and doubletime before the mammalian genes were found (Hardin et al., Nature 1990; Preitner et al., Cell 2002).

  • Often saidA gene test can tell you your chronotype precisely

    ActuallyMorningness-eveningness is shaped by hundreds of common variants, with reported SNP heritability around 13.7% across 351 loci in a 697,828-person meta-analysis. A single-gene readout captures only a sliver and rarely changes what a simple morningness questionnaire would already suggest (Jones et al., Nature Communications 2019).

  • Often saidThe clock was figured out in mammals

    ActuallyIt was decoded first in the fruit fly. Konopka and Benzer's 1971 period mutants and the 1984 cloning of period in Drosophila preceded the mouse Clock gene by a decade or more (Konopka & Benzer, PNAS 1971).

Who profits, and who pushes back

  • Hall, Rosbash & Young

    Promotes itNobel laureates

    Established the molecular clock mechanism; foundational, non-commercial science.

  • Chronobiology researchers

    Promotes itAcademic

    Continue mapping clock-gene variants to chronotype, metabolism, and disease.

  • Joseph S. Takahashi

    Pushes backInvestigator, Howard Hughes Medical Institute; UT Southwestern; led the mouse Clock gene discovery

    Takahashi's group frames clock biology as the product of a complex gene network shaped by hundreds of loci, cautioning against reducing chronotype to any single gene; their genome-wide work positions individual variation as polygenic rather than Mendelian (King et al., Cell 1997; Takahashi reviews).

  • Samuel E. Jones and Michael N. Weedon

    Pushes backGenetic epidemiologists, University of Exeter; lead authors of the 697,828-person chronotype GWAS

    Jones, Weedon and colleagues report that 351 loci together account for only about 13.7% of chronotype variance, with the most extreme morning-allele carriers differing from the fewest by roughly 25 minutes of sleep timing, modest at the individual level (Jones et al., Nature Communications 2019).

  • Akhilesh B. Reddy

    Pushes backCircadian neuroscientist; reported non-transcriptional redox oscillations in anucleate human red blood cells

    Reddy's work shows circadian peroxiredoxin redox rhythms persist in cells without a nucleus or transcription, arguing the gene-based feedback loop is the dominant but not the sole circadian timekeeper (O'Neill & Reddy, Nature 2011).

Where the research comes from

Share of published research by country of origin.
PlaceShare of published research
USA42%
Europe32%
Asia16%
Other10%

Research published from: Global.

How we got here

The molecular clock was decoded first in the fruit fly, not in mammals. In 1971 at Caltech, Ronald Konopka and Seymour Benzer isolated three Drosophila mutants, one arrhythmic, one with a 19-hour cycle, one near 28 hours, all mapping to a single X-chromosome gene they named period. For over a decade the gene was a genetic abstraction. In 1984 two groups, Michael Young at Rockefeller and Jeffrey Hall with Michael Rosbash at Brandeis, cloned period and showed gene transfer could restore rhythm in mutant flies. Hall and Rosbash then found that PER protein rises at night and falls by day, and in 1990 that PER feeds back to repress its own gene, the core feedback loop. Young added the timeless and doubletime genes. Mammalian work followed: Joseph Takahashi's group found the mouse Clock gene by mutagenesis (1994) and cloned it (1997). The 2017 Nobel Prize in Physiology or Medicine recognized Hall, Rosbash, and Young.

  1. 1971Konopka and Benzer isolate three period mutants in Drosophila (arrhythmic, ~19 h, ~28 h), all in one X-chromosome gene (PNAS)
  2. 1984Bargiello, Jackson and Young, and Hall and Rosbash's group, clone the period gene and restore rhythms by gene transfer (Nature, two papers)
  3. 1990Hardin, Hall and Rosbash show PER protein feeds back to repress its own period mRNA, defining the transcription-translation feedback loop (Nature)
  4. 1994Young identifies the timeless gene (TIM); Vitaterna and Takahashi find the mouse Clock mutation by ENU mutagenesis (Science)
  5. 1997King et al. positionally clone mouse Clock, a bHLH-PAS transcription factor; CLOCK:BMAL1 established as the positive arm (Cell)
  6. 2017Nobel Prize in Physiology or Medicine to Hall, Rosbash and Young; Patke and Young link a CRY1 variant to familial delayed sleep phase disorder (Cell)
  7. 2019Jones et al. meta-analysis of 697,828 people maps 351 loci for morningness-eveningness, SNP heritability ~13.7% (Nature Communications)

At a glance

Positive arm
CLOCK : BMAL1
Negative arm
PER : CRY
Loop time
~24 hours
Nobel Prize
2017

What this entry does not yet cover

What follows is unfinished work on our side, not a finding about Clock Genes. A short entry is not a safe entry.

  • Cost and market. We have not documented what it sells for or who sells it.
  • Supply chain. We have not mapped where it is made.
  • Who uses it. We have not documented the user groups.
  • What could change. No forward-looking summary yet.
  • How it compares. We have not set it against the alternatives.
  • Children and teenagers. We have not checked what is known about younger people.

Sources