Evolutionary relevance of single nucleotide variants within the forebrain exclusive human accelerated enhancer regions

BMC Molecular and Cell Biology

article

Hussain, Irfan¹  Shubin, Neil H.²  Abbasi, Amir Ali¹  Khatoon, Hizran¹  Raza, Rabail Zehra³  Saleem, Shoaib¹  Batool, Fatima¹  Arshad, Saba¹  Abrar, Muhammad¹  Ali, Shahid² 

[1] National Center for Bioinformatics, Program of Comparative and Evolutionary Genomics, Faculty of Biological Sciences, Quaid-I-Azam University;Department of Organismal Biology and Anatomy, The University of Chicago;Department of Biological Sciences, National University of Medical Sciences

关键词: Evolution;    Enhancers;    Human accelerated regions;    Forebrain;    Archaic hominins;    TFBS;    SNVs;    SOX2;    HMG box;    EMSA;   

DOI  :  10.1186/s12860-023-00474-5

学科分类：内科医学

来源: Colegio Oficial de Psicologos

【 摘 要 】

Human accelerated regions (HARs) are short conserved genomic sequences that have acquired significantly more nucleotide substitutions than expected in the human lineage after divergence from chimpanzees. The fast evolution of HARs may reflect their roles in the origin of human-specific traits. A recent study has reported positively-selected single nucleotide variants (SNVs) within brain-exclusive human accelerated enhancers (BE-HAEs) hs1210 (forebrain), hs563 (hindbrain) and hs304 (midbrain/forebrain). By including data from archaic hominins, these SNVs were shown to be Homo sapiens-specific, residing within transcriptional factors binding sites (TFBSs) for SOX2 (hs1210), RUNX1/3 (hs563), and FOS/JUND (hs304). Although these findings suggest that the predicted modifications in TFBSs may have some role in present-day brain structure, work is required to verify the extent to which these changes translate into functional variation. To start to fill this gap, we investigate the SOX2 SNV, with both forebrain expression and strong signal of positive selection in humans. We demonstrate that the HMG box of SOX2 binds in vitro with Homo sapiens-specific derived A-allele and ancestral T-allele carrying DNA sites in BE-HAE hs1210. Molecular docking and simulation analysis indicated highly favourable binding of HMG box with derived A-allele containing DNA site when compared to site carrying ancestral T-allele. These results suggest that adoptive changes in TF affinity within BE-HAE hs1210 and other HAR enhancers in the evolutionary history of Homo sapiens might have brought about changes in gene expression patterns and have functional consequences on forebrain formation and evolution. The present study employ electrophoretic mobility shift assays (EMSA) and molecular docking and molecular dynamics simulations approaches.

【 授权许可】

CC BY|CC0