Short answers, pulled from the story.
The CLOCK gene was discovered in 1997 by a team of researchers led by Joseph Takahashi. This team identified a mouse mutant whose internal clock had run so far off schedule that it eventually ceased to function entirely. The gene was named CLOCK as a backronym for circadian locomotor output cycles kaput to reflect the chaotic behavior of the mutant animals.
The CLOCK protein functions as a basic helix-loop-helix-PAS transcription factor that binds to specific DNA sequences to regulate gene expression. In mammals, the CLOCK protein dimerizes with a partner protein called CYCLE or dBMAL1 to bind to E-box elements on the promoters of period and timeless genes. This binding stimulates the expression of these genes, leading to the production of PER and TIM proteins which eventually block the CLOCK-CYC complex from binding to the DNA.
The CLOCK-BMAL dimer activates the transcription of the Nicotinamide phosphoribosyltransferase gene which codes for the NAMPT protein. This protein is part of a series of enzymatic reactions that convert niacin to NAD, a molecule essential for cellular energy. Disruptions in this loop can lead to metabolic syndrome symptoms, altered plasma glucose levels, and disrupted food intake rhythms in mutant mice.
The origins of the CLOCK gene stretch back hundreds of millions of years with its roots embedded in the earliest forms of life. The common ancestor of CLOCK and BMAL1 likely predates the insect-vertebrate split roughly 500 million years ago. Cryptochromes are likely descendants of kaiC resulting from a genome duplication predating the Cambrian explosion.
In humans, the CLOCK gene plays a critical role in the development and function of the brain particularly in the regulation of neuronal migration and cortical expansion. Polymorphisms in the 3111C allele of the 3' flanking region of the CLOCK gene have been linked to morning or evening preference in adults. These polymorphisms can affect mRNA stability and lead to conditions such as insomnia or other sleep disorders.
Mutations in the CLOCK gene can lead to a wide array of physiological and behavioral disorders ranging from sleep disturbances to mood disorders. In humans, a polymorphism in Clock rs6832769 may be related to the personality trait agreeableness while another single nucleotide polymorphism 3111C is associated with diurnal preference and increased insomnia. These mutations are also linked to difficulty losing weight and the recurrence of major depressive episodes in patients with bipolar disorder.