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The PER3 gene encodes the period circadian protein homolog 3 protein in humans.

This gene is a member of the Period family of genes and is expressed in a circadian pattern in the suprachiasmatic nucleus, the primary circadian pacemaker in the mammalian brain. Genes in this family encode components of the circadian rhythms of locomotor activity, metabolism, and behavior. Circadian expression in the suprachiasmatic nucleus continues in constant darkness, and a shift in the light/dark cycle evokes a proportional shift of gene expression in the suprachiasmatic nucleus. The specific function of this gene is not yet known.

History
Attributing the discovery of the discovery of Per3 ortholog to a single person is difficult because two studies claiming to be the first to discover and clone Per3 were both published in June, 1988. Therefore, the discovery of Per3 can most aptly be attributed to the research groups who published these two research papers: A light-independent oscillatory gene mPer3 in mouse SCN and OVLT and Three period Homologs in Mammals: Differential Light Responses in the Suprachiasmatic Circadian Clock and Oscillating Transcripts Outside of Brain”. Mammalian Per3 was discovered by conducting a search for homologous cDNA sequences to Per2. mPER3 is between 37-56% similar to the other two PER proteins, based on varying results from the two papers.

Role in chronobiology
The RNA levels of mPer3 oscillate with a circadian rhythm in both the SCN and in the eyes, as well as in peripheral tissues, including the liver, skeletal muscle, and testis. Unlike Per1 and Per2, of which the mRNA is induced in response to light, Per3 mRNA in the SCN does not respond to light. This suggests that Per3 may be regulated differently than either Per1 or Per2.

The mPER3 protein contains a PAS domain, similar to mPER1 and mPER2. Likely, mPER3 binds to other proteins using this domain. However, while PER1/2 have been shown to be important in the transcription-translation feedback loop involved in the intracellular circadian clock, the influence of PER3 in this loop has not yet been fully elucidated, given that mPER3 does not appear to be functionally redundant to mPER1 and mPER2. Researchers hypothesize that mPer3 may not be important to the core clock loop at all.

Misconceptions
While the Per3 gene is a paralog to the Per1 and Per2 genes, studies in animals generally show that it does not contribute significantly to circadian rhythms. Functional Per3-/- animals experience only small changes in free-running period ,and do not respond significantly differently to light pulses. Per1-/- and Per2-/- animals experience a significant change in free-running period; however, knocking out Per3 in addition to either Per1 or Per2 has little effect on free-running rhythms. Furthermore, Per1-/-Per2-/- mice are completely arrhythmic, indicating that these two genes have much more importance to the biological clock than Per3. Nonetheless, members of the scientific community have shown that, in human studies, polymorphisms in the gene are strongly related with various aspects of circadian rhythms (see Clinical significance).

Studies show that the Per3 knockout mouse experience a slightly shortened period of locomotor activity (0.5h, ), and some further suggest that they may be less sensitive to light, in that they entrain more slowly to changes in the light-dark cycle. These studies suggest that PER3 may be involved in the suppression of behavioral activity in response to light, although mPer3 expression is not necessary for circadian rhythms (van der Veen and Archer, 2010; Pereira et al., 2014).

Clinical significance
The much studied PER3 “length” polymorphism is a structural polymorphism in the 54-bp repeat sequence in exon 18 (GenBank accession no. AB047686) due to an insertion/deletion of 18 amino acids in a region encoding a putative phosphorylation domain. The polymorphism has been associated with diurnal preference and delayed sleep phase syndrome. The longer allele of the polymorphism is associated with “morningness” and the short allele with “eveningness.” The short allele is also associated with delayed sleep phase syndrome. The length polymorphism has also been shown to inhibit adipogenesis and Per3 knockout mice were shown to have increased adipose tissue and decreased muscle tissue compared to wild type.

Per3 has been shown to be strongly associated with “chronotypes, circadian dysfunction, and the homeostatic regulation of sleep.” Recent human studies have correlated the absence of Per3 to affect peripheral oscillators.