A functional MiR-124 binding-site polymorphism in IQGAP1 affects human cognitive performance.

Lixin Yang,Rui Zhang,Xiaodong Shi,Qingwei Li,Ming Li,Lin Huang,Xujun Wu,Jianhong Wang,Bing Su,Zhongming Zhao

doi:10.1371/journal.pone.0107065

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.

Highlights

MicroRNAs are endogenous,21 nt RNAs that play important roles in a variety of biological processes [1]
Several SNPs such as rs363039 and rs17070145, which are located at introns, were shown to have some association with human cognition [36,37] but neither were functional SNPs located at the 39UTR region of a microRNA target gene
We opted to focus on rs1042538, a functional variant residing in a miR-124 binding site of the IQ motif containing GTPase activating protein 1 (IQGAP1) 39UTR

Summary

Introduction

MicroRNAs (miRNAs) are endogenous ,21 nt RNAs that play important roles in a variety of biological processes [1]. Rs1042538 (an A to T substitution) showed suggestive evidence of recent positive selection in an African population (Yoruba in Ibadan, YRI) [6]. This SNP at the position 1 of the miR-124 binding site in the 39UTR of IQGAP1 gene and it is highly conserved in major non-human primate lineages, including chimpanzee, gibbon, rhesus macaque and common marmoset (www.rhesusbase.org; http://asia.ensembl.org). It may affect the binding affinity of miR-124, and eventually lead to possible functional consequences

Methods

Results

Conclusion