title: Recent Positive Selection Drives the Expansion of a Schizophrenia Risk Nonsynonymous Variant at SLC39A8 in Europeans.
abstract: Natural selection has played important roles in optimizing complex human adaptations. However, schizophrenia poses an evolutionary paradox during human evolution, as the illness has strongly negative effects on fitness, but persists with a prevalence of ~0.5% across global populations. Recent studies have identified numerous risk variations in diverse populations, which might be able to explain the stable and high rate of schizophrenia morbidity in different cultures and regions, but the questions about why the risk alleles derived and maintained in human gene pool still remain unsolved. Here, we studied the evolutionary pattern of a schizophrenia risk variant rs13107325 (P < 5.0 × 10(-8) in Europeans) in the SLC39A8 gene. We found the SNP is monomorphic in Asians and Africans with risk (derived) T-allele totally absent, and further evolutionary analyses showed the T-allele has experienced recent positive selection in Europeans. Subsequent exploratory analyses implicated that the colder environment in Europe was the likely selective pressures, ie, when modern humans migrated "out of Africa" and moved to Europe mainland (a colder and cooler continent than Africa), new alleles derived due to positive selection and protected humans from risk of hypertension and also helped them adapt to the cold environment. The hypothesis was supported by our pleiotropic analyses with hypertension and energy intake as well as obesity in Europeans. Our data thus provides an intriguing example to illustrate a possible mechanism for maintaining schizophrenia risk alleles in the human gene pool, and further supported that schizophrenia is likely a product caused by pleiotropic effect during human evolution.
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, China; These authors contributed equally to this work. ML and XJL are co-corresponding authors who jointly directed this work. limingkiz@gmail.com.
authors.forename: Ming
authors.initials: M
authors.lastname: Li
authors.affiliation: State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China; These authors contributed equally to this work.
authors.forename: Dong-Dong
authors.initials: DD
authors.lastname: Wu
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, China; CAS Center for Excellence in Brain Science, Chinese Academy of Sciences, Shanghai, China;
authors.forename: Yong-Gang
authors.initials: YG
authors.lastname: Yao
authors.affiliation: State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China; College of Life Science, Anhui University, Hefei, Anhui, China;
authors.forename: Yong-Xia
authors.initials: YX
authors.lastname: Huo
authors.affiliation: State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China; Kunming College of Life Science, University of Chinese Academy of Sciences, Beijing, China;
authors.forename: Jie-Wei
authors.initials: JW
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China;
authors.forename: Bing
authors.initials: B
authors.lastname: Su
authors.affiliation: Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, US; Division of Genetics, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, US;
authors.forename: Daniel I
authors.initials: DI
authors.lastname: Chasman
authors.affiliation: Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, US;
authors.forename: Audrey Y
authors.initials: AY
authors.lastname: Chu
authors.affiliation: The Department of Nutrition, Harvard School of Public Health, Boston, MA, US;
authors.forename: Tao
authors.initials: T
authors.lastname: Huang
authors.affiliation: The Department of Nutrition, Harvard School of Public Health, Boston, MA, US; The Channing Laboratory and the Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, US.
authors.forename: Lu
authors.initials: L
authors.lastname: Qi
authors.affiliation: The Department of Nutrition, Harvard School of Public Health, Boston, MA, US;
authors.forename: Yan
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, China; These authors contributed equally to this work. ML and XJL are co-corresponding authors who jointly directed this work.
authors.forename: Xiong-Jian
authors.initials: XJ
authors.lastname: Luo
mesh_terms: D000483:Alleles; D044466:Asian People / Q000235:genetics*; D044383:Black People / Q000235:genetics*; D027682:Cation Transport Proteins / Q000235:genetics*; D003080:Cold Temperature; D002149:Energy Intake / Q000235:genetics; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D006973:Hypertension / Q000235:genetics; D009765:Obesity / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D065840:Protective Factors; D012306:Risk; D012559:Schizophrenia / Q000235:genetics*; D012641:Selection, Genetic; D044465:White People / Q000235:genetics*
chemical_list: D027682:Cation Transport Proteins; C530151:SLC39A8 protein, human
keywords: Europe; SLC39A8; nonsynonymous SNP; pleiotropic effects; positive selection; schizophrenia