Genetic diversity patterns at the human clock gene period 2 are suggestive of population-specific positive selection

Abstract

Period 2 (PER2) is a key component of the mammalian circadian clock machinery. In humans, genetic variation of clock genes or chronic disturbance of circadian rhythmicity has been implied in the onset of several phenotypes, ranging from periodic insomnias to advanced or delayed sleep phases, to more severe disorders. Peculiar geographic diversity patterns in circadian genes might represent an adaptive response to different light/dark cycles or environmental changes to which different human populations are exposed. To investigate the degree and nature of PER2 gene variation in human populations of different geographic origin, and its possible correlation with different latitudes, we sequenced a 7.7 kb portion of the gene in 20 individuals worldwide. In total, 25 variable sites were identified. The geographic distribution of haplotypes defined by five polymorphic sites was analyzed in 499 individuals from 11 populations from four continents. No evidence for latitude-driven selective effects on PER2 genetic variability was found. However, a high and significant difference in the geographic distribution of PER2 polymorphisms was observed between Africans and non-Africans, suggesting a history of geographically restricted natural selection at this locus. In support of this notion, we found several signals for selection in the sequences. The putative selected haplotype showed a recent coalescent age (8.7 Kyr), and an unusually high frequency in non-African populations. Overall, these findings indicate that a human clock-relevant gene, PER2, might have been influenced by positive selection, and offer preliminary insights into the evolution of this functional class of genes.

Patterns of Nucleotide Diversity of the ldpA Circadian Gene in Closely Related Species of Cyanobacteria from Extreme Cold Deserts

“…In such a case, the methods of analysis may fail to determine positive selection at the macrolevel due to their insufficient power. In addition, selection may work only in some populations, as was reported for the period 2 gene in humans (56). According to the results of the population history analysis, both S1 and S2 species experienced recent population expansion.…”

Do Caucasian and Asian clocks tick differently?

“…Using a similar strategy but investigating several clock and clock-related genes in five ethnic groups, Ciarleglio et al (17) have reported that is unlikely that a pattern of natural selection has shaped the evolutionary process of these genes, suggesting that a random process is involved. On the other hand, Cruciani et al (19) have suggested that polymorphisms in the PER2 gene might have been influenced by natural selection.…”

“…Based on previous studies and on the present findings (16,17,19) and considering the history of human migrations around the planet over time, as well as the special characteristics of sunshine and light inherent to each place on earth, it is worth questioning which factors contributed to genetic variations that are specific to each ethnic group, especially considering the clock genes. Since the circadian phenotype is a result of strong interaction between the environment and the organism and the most important Zeitgeber for humans is the light/dark cycle given by the sun (15), it would be logical to think that differences in latitude could contribute in an important manner to the selection of these polymorphisms in different geographical zones.…”

Latitudinal clines: an evolutionary view on biological rhythms,

“…One study aimed at finding directional selection on circadian clock genes in humans concluded that the genetic variation among world populations was due to genetic drift rather than latitudinal selection [50]. However, another revealed that genetic [51].…”