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© 2017, Gaspar et al. This work is licensed under the Creative Commons Attribution License ( https://creativecommons.org/licenses/by/3.0/ ) (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

Abstract

The importance of natural gene expression variation for human behavior is undisputed, but its impact on circadian physiology remains mostly unexplored. Using umbilical cord fibroblasts, we have determined by genome-wide association how common genetic variation impacts upon cellular circadian function. Gene set enrichment points to differences in protein catabolism as one major source of clock variation in humans. The two most significant alleles regulated expression of COPS7B, a subunit of the COP9 signalosome. We further show that the signalosome complex is imported into the nucleus in timed fashion to stabilize the essential circadian protein BMAL1, a novel mechanism to oppose its proteasome-mediated degradation. Thus, circadian clock properties depend in part upon a genetically-encoded competition between stabilizing and destabilizing forces, and genetic alterations in these mechanisms provide one explanation for human chronotype.

Details

Title
The genomic landscape of human cellular circadian variation points to a novel role for the signalosome
Author
Gaspar Ludmila; Howald Cedric; Popadin Konstantin; Maier, Bert; Mauvoisin, Daniel; Moriggi Ermanno; Gutierrez-Arcelus, Maria; Falconnet Emilie; Borel Christelle; Kunz, Dieter; Kramer, Achim; Gachon Frederic; Dermitzakis, Emmanouil T; Antonarakis, Stylianos E; Brown, Steven A
University/institution
U.S. National Institutes of Health/National Library of Medicine
Publication year
2017
Publication date
2017
Publisher
eLife Sciences Publications Ltd.
e-ISSN
2050084X
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
1950551884
Copyright
© 2017, Gaspar et al. This work is licensed under the Creative Commons Attribution License ( https://creativecommons.org/licenses/by/3.0/ ) (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.