Per3 — Clock Gene or Sleep Gene?

Whereas invertebrates such as Drosophila only have one Period gene, mammals such as humans have three paralogues ( Perl, Per2 , and Per3 ). This, as many other gene families, is one of many results of two proposed genome duplication events early in vertebrate evolution (the so-called 2R hypothesis). Typically, in these instances, the duplicated gene products take on different roles. This diversity has been suggested to be a major contributor to the increased anatomic and physiological complexity of the vertebrates. By comparing the neighbouring gene clusters, and intron/exon structure, we were able to reveal evidence for a common origin, followed by duplication, of the human PER genes. Data from double knockout mouse models have shown that, whereas Perl or Per2 are each individually to sustain circadian rhythmicity in the absence of all other paralogues, Per3 is neither necessary nor sufficient for circadian rhythms. Of crucial importance for our work in trying to understand better the function of Per3 has been a variable number tandem repeat (VNTR) polymorphism in the coding region of the human PER3 gene. The two alleles of this polymorphism encode either four or five repeats of an 18-amino-acid unit. In our initial study, we found moderate but significant associations between the shorter allele ( PER3 4 ) and evening preference and delayed sleep phase disorder (DSPD), and between the longer allele ( PER3 5 ) and morning preference. We subsequently designed a prospective study, where we compared matched volunteers who were homozygous for the two different alleles. No difference were found in amplitude or phase of circadian parameters, including melatonin an cortisol levels and clock gene expression in peripheral leukocytes, disproving our initial hypothesis. Instead, we found considerable differences in sleep homeostasis and tolerance to sleep deprivation between the two groups. The PER3 5 homozygotes had a significantly shorter sleep latency, more slow-wave sleep during baseline sleep, and less non-REM sleep following sleep deprivation. During sleep deprivation, they had a considerably greater decrement in cognitive performance than the PER3 4 homozygotes. Thus, the PER3 5 homozygotes could be described as living under a higher sleep pressure. In conclusion, our findings indicate that the Per3 gene is more involved with sleep homeostasis than with circadian rhythms. Such a shift in function is entirely consistent with the 2R model of gene duplication. Publication History Article published online: 16 June 2026 © 2009. Brazilian Sleep Academy. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/) Thieme Revinter Publicações Ltda. Rua Rego Freitas, 175, loja 1, República, São Paulo, SP, CEP 01220-010, Brazil