Demographic history and adaptation account for clock gene diversity in humans

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 FST 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.