Demographic history and adaptation account for clock gene diversity in humans

Abstract

Circadian clocks give rise to daily oscillations in behavior and physiological functions that often anticipate upcoming environmental changes generated by the Earth rotation. In model organisms a relationship exists between several genes affecting the circadian rhythms and latitude. We investigated the allele distributions at 116 000 single-nucleotide polymorphisms (SNPs) of 25 human clock and clock-related genes from the 1000Genomes Project, and at a reference data set of putatively neutral polymorphisms. The global genetic structure at the clock genes did not differ from that observed at the reference data set. We then tested for evidence of local adaptation searching for F ST outliers under both an island and a hierarchical model, and for significant association between allele frequencies and environmental variables by a Bayesian approach. A total of 230 SNPs in 23 genes, or 84 SNPs in 19 genes, depending on the significance thresholds chosen, showed signs of local adaptation, whereas a maximum of 190 SNPs in 23 genes had significant covariance with one or more environmental variables. Only two SNPs from two genes (NPAS2 and AANAT) exhibit both elevated population differentiation and covariance with at least one environmental variable. We then checked whether the SNPs emerging from these analyses fall within a set of candidate SNPs associated with different chronotypes or sleep disorders. Correlation of five such SNPs with environmental variables supports a selective role of latitude or photoperiod, but certainly not a major one. Heredity At the molecular level, the circadian clock involves interlocked positive and negative transcriptional/translational feedback loops between clock genes and their protein products, together with a multilevel post-translational regulation of key clock components (Mohawk et al., 2012). In mammals the positive loop is formed by the basic HLH-PAS proteins CLK (or its paralog NPAS2) and BMAL that heterodimerize and bind E-box elements in the regulatory regions of the Period (Per) and Cryptochrome (Cry) genes. The negative feedback loop is constituted by PER/CRY heterodimers that repress their own transcription by inhibiting CLK/BMAL activity. Moreover, the CLK/BMAL complex activates the transcription of two nuclear receptors, Rev-Erbα and Rora, the protein products of which regulate Bmal1 expression to bind retinoic acid-related orphan receptor response elements in the Bmal1 promoter. Post-transcriptional modifications (such as phosphorylation, ubiquitination, sumoylation) are also crucial in the regulation of circadian protein turnover

The End of Snoring? Application of CRISPR/Cas9 Genome Editing for Sleep Disorders

“…Furthermore, Hu et al (2016) reported that a GWAS analysis of self-reported morningness showed 15 significantly associated loci, including seven circadian genes [52]. These findings as well as other reports [53][54][55][56][57] suggest that genes with circadian expression may play a critical role in regulating both the circadian clock and sleep homeostasis as well as circadian-related sleep disturbances such as advanced sleep phase syndrome (Table 1).…”

Latitudinal differences on the global epidemiology of infantile spasms: systematic review and meta-analysis

“…If indeed the latitudinal effect exists, ultraviolet radiation (UVR), which is received in an inverse latitudinal manner, may be the relevant environmental agent. Environmental-neurophysiological interfaces have already been established in mice with seasonally-related, light-induced, mTOR and BDNF signalling-related dendritic morphologic adaptation [ 78 ], while UVR’s neurological role is thought to involve at least sleep duration [ 79 ], clock gene diversity [ 80 ], and development of multiple sclerosis [ 81 ]. In the case of IS, the UVR-epileptic interaction may be mediated by Vitamin D3, the secosteroid synthesized cutaneously in an UVR-dependent fashion, although infants primarily derive it from maternal contribution [ 82 ].…”

Whole genome SNP-associated signatures of local adaptation in honeybees of the Iberian Peninsula

“…While longitude and latitude do not act directly on organisms, they serve as composite variables representing multiple environmental factors, any one or a combination of which could be exerting parallel selective forces. Latitude has been found to be associated with circadian clock genes in Drosophila 78 – 81 and humans 82 , 83 , and now in honeybees. Clock genes are tagged by SNPs forming latitudinal and longitudinal gradients in Iberia.…”