褪黑激素通路是生物节律信号转导的主要途径之一，受环境日/夜周期影响。世界范围内不同的日照时长及相应的昼夜节律的自然选择作用很可能对褪黑激素通路的遗传多态起着重要的作用。
在中国科学院昆明动物研究所张亚平院士及香港中文大学邓亮生教授的共同指导下，博士研究生季林丹等研究人员对世界人群（CEPH-HGDP）褪黑激素通路基因多态性与日照时长的相关性进行了系统分析。研究提示，在全世界范围内人群中褪黑激素受体MT2（MTNR1B）基因的多态性与日照密切相关，该研究结果同时在中国群体中得到验证。因此，褪黑激素通路，尤其MT2受体的遗传多态性很可能经历了日照的自然选择。
此外，该遗传多态性在前期与香港中文大学的合作研究中发现与青少年特发性脊柱侧凸（Adolescent Idiopathic scoliosis, AIS）发病相关；近期报道的全基因组研究（GWAS）也提示其为二型糖尿病(Type 2 Diabetes Mellitus, T2D)的易感位点。
综合研究结果提示，日照时长的自然选择作用可能促使形成了MTNR1B基因遗传位点的多态；但随着自然环境及生活方式的改变，该多态性反而可能成为疾病易感因素。该研究是阐释复杂疾病易感位点经历环境自然选择假说的一次成功示例，更重要是也可为二型糖尿病及青少年特发性脊柱侧凸等疾病临床诊治等提供新的信息。
该研究结果近期发表在Journal of Pineal Research上。
推荐原文出处：
Journal of Pineal Research doi:10.1111/j.1600-079X.2009.00736.x
Association of disease-predisposition polymorphisms of the melatonin receptors and sunshine duration in the global human populations
Lin-dan Ji 1,2,3*, Jin Xu 4*, Dong-dong Wu 2,5 , Si-da Xie 3,6 , Nelson L. S. Tang 3,6,7 and Ya-ping Zhang 2,3,8
1 Department of Biochemistry and Genetics, School of Medicine, Zhejiang University, Hangzhou, China ; 2 State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China ; 3 KIZ/CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming, China ; 4 Institute of Public Health, School of Medicine, Ningbo University, Ningbo, China ; 5 Graduate School of the Chinese Academy of Sciences, Beijing, China ; 6 Department of Chemical Pathology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China ; 7 Laboratory for Genetics of Disease Susceptibility, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China ; 8 Laboratory for Conservation and Utilization of Bio-resource, Yunnan University, Kunming, China
Abstract: Melatonin is predominantly involved in signaling circadian and seasonal rhythms, and its synthesis is regulated by the environmental light/dark cycle. The selection pressure by geographically different environmental light/dark cycles, which is predominantly determined by sunshine duration, on the global distribution of genetic polymorphisms in the melatonin pathway is not well understood. Recent genetic association studies identified various disease-predisposition polymorphisms in this pathway. We investigated the correlations between the prevalence of these clinically important single nucleotide polymorphisms (SNPs) and sunshine duration among worldwide human populations from twelve regions in the CEPH-HGDP database rs4753426, a recently reported predisposition SNP for type 2 diabetes in the promoter of the MT2 melatonin receptor gene (MTNR1B), which was not included in the CEPH-HGDP genotyping array, was additionally genotyped. This SNP showed a marginally significant correlation in 760 CEPH-HGDP DNA samples (r = ?0.5346, P = 0.0733), and it showed the most prominent association among the candidate melatonin pathway SNPs examined. To control for population structure, which may lead to a false positive correlation, we genotyped this SNP in a replication set of 1792 subjects from China. The correlation was confirmed among Chinese populations (r = ?0.8694, P = 0.0002), and was also statistically significant after correction of other climatic and geographical covariants in multiple regression analysis (β = ?0.907, P = 1.94 × 10?5). Taken together, it suggests that the human melatonin signaling pathway, particularly MT2 melatonin receptor may have undergone a selective pressure in response to global variation in sunshine duration.
