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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Genet. | doi: 10.3389/fgene.2019.00152

Evolution and Comprehensive Analysis of DNaseI Hypersensitive Sites in Brain-Related Genes Regulatory Regions of Primates

 Yueer Lu1,  Xiao Wang2, Hang Yu1, Jianlin Li1, Zhiqiang Jiang1, Bangwei Chen1, Yueqi Lu1, Chongyin Han1,  Wei Wang1, Ying Ouyang1, Lizhen Huang1, Chunbo Chen3*,  Weidong Tian2* and  Fei Ling1*
  • 1South China University of Technology, China
  • 2Fudan University, China
  • 3Guangdong Provincial People's Hospital, China

How human brain differs from non-human primates is largely unknown and the complex drivers on genomic scope remain unclear. In this study, we selected 243 brain-related genes in Gene Ontology and leveraged 184,113 DNaseI hypersensitive sites (DHSs) within their regulatory regions. As a result, 2397 DHSs (6%) were accelerated evolved (aceDHSs), of which was much higher compared to genome-wide scale. Regulated targets of brain-aceDHSs were enriched in brain development and exhibited differential expression between human and chimpanzee. Through alignment, 61 potential human-specific transcription factor binding sites located in brain-aceDHSs, including CTCF, FOXH1 and FOXQ1. Furthermore, based on GWAS, Hi-C and eQTL data, 16 GWAS SNPs and 82 eQTL SNPs were located in brain-aceDHSs and regulated genes that related with brain development or diseases. Among brain-aceDHSs, using both CRISPR-Cas9 and western blotting, we confirmed that one aceDHS enhanced the expression of GPR133, a gene that influenced glioblastoma, indicating variants within DHSs could be potential SNPs of brain disorders. These findings suggested that brain-related gene regulatory regions are under adaptive evolution and contribute to the differential expression profiles among primates, providing new insights into the genetic basis of brain phenotypes or disorders between humans and other primates.

Keywords: Brain, DNaseI Hypersensitive Sites, evolution, Primates, Regulatory regions

Received: 19 Dec 2018; Accepted: 13 Feb 2019.

Edited by:

James J. Cai, Texas A&M University, United States

Reviewed by:

Vladimir I. Vladimirov, VCU Medical Center, United States
Courtney Babbitt, University of Massachusetts Amherst, United States  

Copyright: © 2019 Lu, Wang, Yu, Li, Jiang, Chen, Lu, Han, Wang, Ouyang, Huang, Chen, Tian and Ling. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Dr. Chunbo Chen, Guangdong Provincial People's Hospital, Guangzhou, China, gghccm@163.com
Prof. Weidong Tian, Fudan University, Shanghai, 200433, Shanghai Municipality, China, weidong.tian@fudan.edu.cn
Prof. Fei Ling, South China University of Technology, Guangzhou, 510 641, Guangdong Province, China, fling@scut.edu.cn