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.

Changes in the Synaptic Proteome in Tauopathy and Rescue of Tau-Induced Synapse Loss by C1q Antibodies

“…To test the functional significance of altered levels of PSD proteins in Tau-P301S mice, we focused on the downregulated ''small GTPase-mediated signal transduction'' pathway. This pathway contains a number of GTPase-regulating proteins (Iqgap1, Iqgap2, Iqsec2, Kalirin, and Trio; Figure 2A), where variants in the underlying genes are associated with epilepsy, autism, schizophrenia, or intellectual disability (De Rubeis et al, 2014;Russell et al, 2014;Sadybekov et al, 2017;Shoubridge et al, 2010;Yang et al, 2014).…”

Role of MicroRNA in Governing Synaptic Plasticity

“…This interaction is further involved in regulating the actin cytoskeleton in plasticity of synapse connections, which refers to dual modes: on one hand, RhoG is available to inhibit dendritic tree complexity via the small GTPase Cdc42 in hippocampal neuron; on the other hand, RhoG is pointed out to repress axonal branching and targeting dependent on the ELMO/Dock180/Rac1 signaling pathway [ 93 – 95 ]. Several groups have identified that the intelligence quotient motif containing GTPase activating protein 1 (IQGAP1), a broadly expressed scaffold protein in brain, acted as a suppressed target of miRNA-124 to regulate hippocampal LTP, long-term memory formation, and cognitive performance [ 96 , 97 ]. Moreover, in cultured neurons of Aplysia sensorimotor synapses, miRNA-124 is localized exclusively to the presynaptic sensory neuron but found deficiently in motor neuron.…”

Combined Experimental and System-Level Analyses Reveal the Complex Regulatory Network of miR-124 during Human Neurogenesis

“…miRNAs bind in a sequence-specific manner to mRNA transcripts and thereby negatively interfere with the simultaneous translation of multiple target transcripts by annealing predominantly at the 3′ untranslated region (UTR). miR-124 is one of the most abundant miRNAs in the brain and is associated with processes such as neurogenesis ( Lagos-Quintana et al., 2002 , Landgraf et al., 2007 ), cancer ( Silber et al., 2008 , Taniguchi et al., 2015 ), and the control of synaptic functions in mature neurons in health ( Dutta et al., 2013 , Hou et al., 2015 , Rajasethupathy et al., 2009 ) and disease ( Fang et al., 2012 , Lukiw, 2007 ) including cognitive impairment ( Gascon et al., 2014 , Yang et al., 2014 ).…”