Cognitive endophenotypes of modern and extinct hominins associated with NTNG gene paralogs

Pavel Prosselkov,Kazutaka Ohi,Masatoshi Takeda,Thomas J Mchugh,Denis Polygalov,Qi Zhang,Shigeyoshi Itohara,Ryota Hashimoto

doi:10.15761/bgg.1000103

Abstract

A pair of gene paralogs, NTNG1 and NTNG2, contributes to the Intellectual Quotient (IQ) test scores in a complementary manner. Single nucleotide polymorphisms (SNPs) of NTNG1 are associated with attenuated verbal comprehension (VC) or processing speed (PS) while NTNG2 SNPs affect working memory (WM) and perceptual organization (PO) forming cognitive endophenotypes in healthy and schizophrenia (SCZ) affected human subjects. Regions of interest (ROIs), defined as 21 nucleotide (nu) long loci embedding the IQ affecting mutation alleles (VC and WM/PO), underwent dramatic evolutionary changes from mice through primates to hominin genes at the accelerated rates. Mutation alleles associated with the higher VC and WM IQ scores are found in the genomes of extinct hominins of Neolithic times, however, lower WM scores associated allele is also detectable in Mesolithic hunters genomes. Protein sequence of NTNG1 is 100% conserved among the archaic and modern extinct hominins while NTNG2 underwent a recent selection sweep encoding a primate-specific S371A/V (~50,000 yrs BC), and a modern human (5,300 yrs BC) T346A substitutions. We show that a 500 mln yrs old genomic duplication of a synapse primordial gene of an urochordate provided a substrate for further synapse elaborations and its ultimate capacitive expansion of what evolved into a vertebrate cognitive superior complexity, intelligence.

Highlights

S.Ohno ingeniously proposed that new gene function can result from gene duplication and following it gene paralogs subfunctionalisation (SF) [1]
Since both NTNG paralogs have been reportedly associated with SCZ [27,28,29,30,31,32,33,34,35] we investigated whether these gene paralogs contribute to human intelligence by assessing the Intelligence Quotient (IQ) of human carriers for the NTNG1 and NTNG2 Single nucleotide polymorphisms (SNPs) alleles against noncarriers with and without SCZ
Prosselkov P (2016) Cognitive endophenotypes of modern and extinct hominins associated with NTNG gene paralogs ex1 int exon 2 (1-2)

Summary

Introduction

S.Ohno ingeniously proposed that new gene function can result from gene duplication and following it gene paralogs subfunctionalisation (SF) [1]. NTNG1 and NTNG2, expressed predominantly in the brain [2], and encoding Netrin-G1 and Netrin-G2 proteins, respectively, are expressed pre-synaptically and segregate in a non-overlapping manner into distinct neuronal circuits [3,4]. They are related to the netrin family of axonal guidance cues [5] but differ in that they attach to the axonal membrane via a glycosylphosphatidylinositol (GPI) link [6,7], a known lipid raftassociated membrane signaling cascade organiser [6,8]. Since both NTNG paralogs have been reportedly associated with SCZ [27,28,29,30,31,32,33,34,35] we investigated whether these gene paralogs contribute to human intelligence by assessing the IQ of human carriers for the NTNG1 and NTNG2 SNP alleles against noncarriers with and without SCZ

Methods

Results

Discussion

Conclusion