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Cell. 2016 Oct 6;167(2):341-354.e12. doi: 10.1016/j.cell.2016.08.071. Epub 2016 Sep 22.

Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior.

Author information

1
Division of Genetics and Genomics, Manton Center for Orphan Disease Research, and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA.
2
Department of Molecular Biology, Centro de Biología Molecular 'Severo Ochoa', Universidad Autonoma de Madrid, UAM-CSIC, Nicolas Cabrera 1, 28049 Madrid, Spain; Department of Molecular and Cellular Biology, Centro Nacional de Biotecnología, CNB-CSIC, Darwin 3, Campus de Cantoblanco, 28049 Madrid, Spain.
3
Kuwait Center for Autism, 73455 Kuwait City, Kuwait.
4
Istanbul Institute of Child and Adolescent Psychiatry, 34365 Istanbul, Turkey.
5
Department of Child and Adolescent Psychiatry, Bahcesehir University School of Medicine, 34353 Istanbul, Turkey.
6
Division of Genetics and Genomics, Manton Center for Orphan Disease Research, and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, College of Medicine and Health Sciences, United Arab Emirates University, PO Box 17666, Al-Ain, United Arab Emirates.
7
Department of Pediatrics, King Faisal Specialist Hospital and Research Center, Jeddah 21499, Kingdom of Saudi Arabia.
8
Department of Neurology (Pediatric Neurology), Massachusetts General Hospital, Boston, MA 02114, USA.
9
Department of Molecular and Cellular Biology, Centro Nacional de Biotecnología, CNB-CSIC, Darwin 3, Campus de Cantoblanco, 28049 Madrid, Spain.
10
Division of Genetics and Genomics, Manton Center for Orphan Disease Research, and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: christopher.walsh@childrens.harvard.edu.

Abstract

Comparative analyses have identified genomic regions potentially involved in human evolution but do not directly assess function. Human accelerated regions (HARs) represent conserved genomic loci with elevated divergence in humans. If some HARs regulate human-specific social and behavioral traits, then mutations would likely impact cognitive and social disorders. Strikingly, rare biallelic point mutations-identified by whole-genome and targeted "HAR-ome" sequencing-showed a significant excess in individuals with ASD whose parents share common ancestry compared to familial controls, suggesting a contribution in 5% of consanguineous ASD cases. Using chromatin interaction sequencing, massively parallel reporter assays (MPRA), and transgenic mice, we identified disease-linked, biallelic HAR mutations in active enhancers for CUX1, PTBP2, GPC4, CDKL5, and other genes implicated in neural function, ASD, or both. Our data provide genetic evidence that specific HARs are essential for normal development, consistent with suggestions that their evolutionary changes may have altered social and/or cognitive behavior. PAPERCLIP.

KEYWORDS:

ASD; Autism; Brain Evolution; HARs; Human Accelerated regions; noncoding

Comment in

PMID:
27667684
PMCID:
PMC5063026
DOI:
10.1016/j.cell.2016.08.071
[Indexed for MEDLINE]
Free PMC Article

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