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. 2017 Jun 26;12(6):e0178373.
doi: 10.1371/journal.pone.0178373. eCollection 2017.

An Ancestral Haplotype of the Human PERIOD2 Gene Associates With Reduced Sensitivity to Light-Induced Melatonin Suppression

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Free PMC article

An Ancestral Haplotype of the Human PERIOD2 Gene Associates With Reduced Sensitivity to Light-Induced Melatonin Suppression

Tokiho Akiyama et al. PLoS One. .
Free PMC article

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.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. SNPs examined in the PER2 gene and frequencies of the haplotypes in the global populations.
(A) Relative map for the six SNPs examined. The SNPs examined in this study are numbered serially, and their rs numbers, alleles reported, and allele frequencies of JPT in the HapMap database are shown. For the SNP6, the amino acid change (Gly/Glu) has been reported in dbSNP. (B) Ancestral allele frequencies of SNPs in PER2. The allele frequency data from Japan are divided into four groups: subjects with physiological data, Northern Kyushu, Ryukyu, and JPT. Those are compared to three approximate geographic populations: East Asia (CHB, CHS), Europe (CEU, FIN, GBR, IBS, TSI) and Africa (LWK, YRI) from the 1000 Genomes Project database. (C) Haplotype frequencies of PER2 in each geographical region. The numbers of local populations included in the geographical region are shown in parentheses. The N represents the numbers of the individuals. The combined frequencies of the remaining haplotype (Residuals) are less than 1.0% in all the geographical regions, indicating that each haplotype in the residual is extremely uncommon among the samples examined.
Fig 2
Fig 2. Comparison of the distributions of percentages of melatonin suppression for three major haplotypes of the PER2 locus.
Thick middle lines in the boxes represent the medians, the tops and bottoms of the boxes represent the third and the first quartiles, respectively, and the lower and upper error bars indicate the minimum and the maximum values. One dot represents one chromosome, and the numbers of chromosomes, n, are shown in parentheses. The Kruskal-Wallis test and Scheffe’s method of multiple comparison tests were performed, and the pairs of Hap1-Hap3 and Hap2-Hap3 revealed significant differences.
Fig 3
Fig 3. Comparison of the distributions of melatonin suppression for the genotypes of PER2.
The thick middle lines in the boxes represent the medians, the tops and bottoms of the boxes represent the third and the first quartiles, respectively, and the lower and upper error bars indicate the minimum and the maximum values. One dot represents one subject, and the numbers of individuals, N, are shown in the parentheses. In the case of heterozygote, differently colored dots represent different genotypes. The Kruskal-Wallis test and Scheffe’s method of multiple comparison tests were conducted, and the pairs of Hap1-Hap3 and Hap2-Hap3 homozygotes showed significant differences.
Fig 4
Fig 4. Phylogenetic network for PER2 haplotypes.
The circles represent the haplotypes, and the circle size is proportional to the sum of the number of chromosomes in all the populations for each haplotype. The pie charts show the haplotype frequencies in each geographical region: three populations from East Asia (JPT, CHB, CHS), five from Europe (CEU, FIN, GBR, IBS, TSI), and two from Africa (LWK, YRI). The minor haplotypes (<1.0%) are omitted here.

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Grant support

HI was supported by Grants-in-Aid for Scientific Research (B) (22370087) from the Japan Society for the Promotion of Science (JSPS) and University of the Ryukyus Strategic Research Grant. SH was supported by Grant-in-Aid for Scientific Research (B) (24370102) from JSPS. AY and HO were supported by Grant-in-Aid for Scientific Research (A) (25251046) from JSPS. HO was supported by Grant-in-Aid for Scientific Research (B) (24370099) from JSPS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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