An ancestral haplotype of the human PERIOD2 gene associates with reduced sensitivity to light-induced melatonin suppression

Abstract

Humans show various responses to the environmental stimulus in individual levels as “physiological variations.” However, it has been unclear if these are caused by genetic variations. In this study, we examined the association between the physiological variation of response to light-stimulus and genetic polymorphisms. We collected physiological data from 43 subjects, including light-induced melatonin suppression, and performed haplotype analyses on the clock genes, PER2 and PER3, exhibiting geographical differentiation of allele frequencies. Among the haplotypes of PER3, no significant difference in light sensitivity was found. However, three common haplotypes of PER2 accounted for more than 96% of the chromosomes in subjects, and 1 of those 3 had a significantly low-sensitive response to light-stimulus (P < 0.05). The homozygote of the low-sensitive PER2 haplotype showed significantly lower percentages of melatonin suppression (P < 0.05), and the heterozygotes of the haplotypes varied their ratios, indicating that the physiological variation for light-sensitivity is evidently related to the PER2 polymorphism. Compared with global haplotype frequencies, the haplotype with a low-sensitive response was more frequent in Africans than in non-Africans, and came to the root in the phylogenetic tree, suggesting that the low light-sensitive haplotype is the ancestral type, whereas the other haplotypes with high sensitivity to light are the derived types. Hence, we speculate that the high light-sensitive haplotypes have spread throughout the world after the Out-of-Africa migration of modern humans.

Impact of seasons on an individual&rsquo;s chronotype: current perspectives

“…PER2 gene variants that confer greater circadian light sensitivity have arisen since modern humans migrated from Africa. 77 Genetic variation in PER2 , OPN4, and PER3 , as well as differences in eye pigmentation, and endogenous circadian period lead to differences in individual anticipation and responsiveness to seasonal change, and seasonality in humans. Many of these variations are related to geographical area of origin and thus may have had an adaptive advantage for the seasonal variations in those regions.…”

“… 74 – 76 Polymorphisms in the clock-associated PER2 gene have been found that account for variation in the magnitude of light-induced melatonin suppression. 77 Interestingly, the ancestral PER2 haplotype (a particular combination of the single nucleotide polymorphism [SNP] rs4663302, rs147573126, rs190386281, rs142175638, rs11894535, and rs934945 variants within the PER2 gene) conferred low light sensitivity and was more frequently found inside Africa than outside Africa, and there was more diversity in PER2 variants in non-African populations than in African populations. 77 Cruciani et al analyzed variations in a 7.7 kb region of the PER2 locus in individuals from five continents.…”

“… 77 Interestingly, the ancestral PER2 haplotype (a particular combination of the single nucleotide polymorphism [SNP] rs4663302, rs147573126, rs190386281, rs142175638, rs11894535, and rs934945 variants within the PER2 gene) conferred low light sensitivity and was more frequently found inside Africa than outside Africa, and there was more diversity in PER2 variants in non-African populations than in African populations. 77 Cruciani et al analyzed variations in a 7.7 kb region of the PER2 locus in individuals from five continents. 78 While they found no evidence of latitudinal selection at the locus, they did find distinct genetic differences between Africans and non-Africans and selection signals suggesting strong geographical natural selection.…”

Chronotype Genetic Variant in PER2 is Associated with Intrinsic Circadian Period in Humans

“…Furthermore, chronotype cannot distinguish among different biological causes, such as differences in endogenous circadian period, circadian rhythm robustness, circadian light sensitivity, and homeostatic sleep regulation time constants. For example, the recent finding that PER2 is associated with reduced sensitivity of the circadian pacemaker to light in humans 34 , highlights the relative benefits of biological measures of circadian rhythmicity in studying the potential mechanisms underlying chronotype differences. Circadian period provides a plausible biological mechanism of the link between the PER2 variant and chronotype, and also provides testable hypotheses for future molecular mechanism studies in animal and in vitro models.…”

Smith-Magenis Syndrome: Molecular Basis of a Genetic-Driven Melatonin Circadian Secretion Disorder

“…Indeed, the genes of the clock system seem to be involved in the light-driven circadian rhythm of melatonin secretion. For example, a haplotype of the Per 2 gene is associated with a clear decrease in the blocking effect of light on melatonin [75]. The CLOCK gene also seems to be involved in the rhythm of melatonin secretion.…”