title: A functional MiR-124 binding-site polymorphism in IQGAP1 affects human cognitive performance.
abstract: As a product of the unique evolution of the human brain, human cognitive performance is largely a collection of heritable traits. Rather surprisingly, to date there have been no reported cases to highlight genes that underwent adaptive evolution in humans and which carry polymorphisms that have a marked effect on cognitive performance. IQ motif containing GTPase activating protein 1 (IQGAP1), a scaffold protein, affects learning and memory in a dose-dependent manner. Its expression is regulated by miR-124 through the binding sites in the 3'UTR, where a SNP (rs1042538) exists in the core-binding motif. Here we showed that this SNP can influence the miR-target interaction both in vitro and in vivo. Individuals carrying the derived T alleles have higher IQGAP1 expression in the brain as compared to the ancestral A allele carriers. We observed a significant and male-specific association between rs1042538 and tactile performances in two independent cohorts. Males with the derived allele displayed higher tactual performances as compared to those with the ancestral allele. Furthermore, we found a highly diverged allele-frequency distribution of rs1042538 among world human populations, likely caused by natural selection and/or recent population expansion. These results suggest that current human populations still carry sequence variations that affect cognitive performances and that these genetic variants may likely have been subject to comparatively recent natural selection.
authors.affiliation: State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China; Kunming College of Life Science, University of Chinese Academy of Sciences, Beijing, China.
authors.forename: Lixin
authors.initials: L
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China; Kunming College of Life Science, University of Chinese Academy of Sciences, Beijing, China.
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, China; Kunming College of Life Science, University of Chinese Academy of Sciences, Beijing, China.
authors.forename: Xujun
authors.initials: X
authors.lastname: Wu
authors.affiliation: Laboratory of Primate Neuroscience Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China.
authors.forename: Jianhong
authors.initials: J
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Huang
authors.affiliation: Department of Biochemistry, Qujing Normal University, Qujing, China.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Shi
authors.affiliation: College of Life Science, Liaoning Normal University, Dalian, China.
authors.forename: Qingwei
authors.initials: Q
authors.lastname: Li
authors.affiliation: State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Su
mesh_terms: D001665:Binding Sites; D003071:Cognition; D015331:Cohort Studies; D019143:Evolution, Molecular; D005260:Female; D005787:Gene Frequency; D006801:Humans; D008297:Male; D008568:Memory; D035683:MicroRNAs / Q000502:physiology*; D020641:Polymorphism, Single Nucleotide; D012737:Sex Factors; D014888:Wechsler Scales; D020703:ras GTPase-Activating Proteins / Q000737:chemistry / Q000235:genetics*
chemical_list: C101203:IQ motif containing GTPase activating protein 1; C509207:MIRN124 microRNA, human; D035683:MicroRNAs; D020703:ras GTPase-Activating Proteins