Natural Variation in Human Clocks

Malcolm von Schantz*

*Corresponding author for this work

Research output: Chapter in Book/Report/Conference proceedingChapterpeer-review

21 Citations (Scopus)


Our own species has a diurnal activity pattern and an average circadian period of 24.2 h. Exact determination of circadian period requires expensive and intrusive protocols, and investigators are therefore using chronotype questionnaires as a proxy quantitative measure. Both measures show a normal distribution suggestive of a polygenic trait. The genetic components of the 24-h feedback loop that generates circadian rhythms within our cells have been mapped in detail, identifying a number of candidate genes which have been investigated for genetic polymorphisms relating to the phenotypic variance. Key in this mechanism is the inhibitory complex containing period and cryptochrome proteins and interacting protein kinases and ubiquitin ligases, and the stability of this complex is recognized as the major determinant of circadian periodicity. The identification of the causative mutations in familial circadian rhythms sleep disorders has shed additional light into this mechanism. Mutations in the negative feedback protein-encoding genes PER2 and CRY2 as well as the CSNK1D gene encoding casein kinase I delta have been shown to cause advanced sleep phase disorder, and a mutation in the CRY1 gene delayed sleep phase disorder. The candidate gene approach has also yielded a number of genetic associations with chronotype as determined by questionnaires. More recently, genome-wide association studies of chronotype have both confirmed associations with the candidate clock gene PER2 and identified a serious of novel genes associated with variability in circadian rhythmicity, which have yet to be explored. While considerable progress has thus been made with mapping the phenotypic diversity in human circadian rhythms and the genomic variability that causes it, studies to date have been mostly focused on individuals of European descent, and there is a strong need for research on other populations.

Original languageEnglish
Title of host publicationAdvances in Genetics
EditorsStephen F. Goodwin
Place of PublicationCambridge, MA
PublisherAcademic Press Inc.
Number of pages24
ISBN (Print)9780128118115
Publication statusPublished - 2017
Externally publishedYes

Publication series

NameAdvances in Genetics
ISSN (Print)0065-2660


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