Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior.
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.
Division of Genetics and Genomics, Manton Center for Orphan Disease Research, and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA.
Ryan N
RN
Doan
Division of Genetics and Genomics, Manton Center for Orphan Disease Research, and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA.
Byoung-Il
BI
Bae
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.
Beatriz
B
Cubelos
Division of Genetics and Genomics, Manton Center for Orphan Disease Research, and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA.
Cindy
C
Chang
Division of Genetics and Genomics, Manton Center for Orphan Disease Research, and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA.
Amer A
AA
Hossain
Kuwait Center for Autism, 73455 Kuwait City, Kuwait.
Samira
S
Al-Saad
Istanbul Institute of Child and Adolescent Psychiatry, 34365 Istanbul, Turkey.
Nahit M
NM
Mukaddes
Department of Child and Adolescent Psychiatry, Bahcesehir University School of Medicine, 34353 Istanbul, Turkey.
Ozgur
O
Oner
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.
Muna
M
Al-Saffar
Department of Pediatrics, King Faisal Specialist Hospital and Research Center, Jeddah 21499, Kingdom of Saudi Arabia.
Soher
S
Balkhy
Department of Neurology (Pediatric Neurology), Massachusetts General Hospital, Boston, MA 02114, USA.
Generoso G
GG
Gascon
Department of Molecular and Cellular Biology, Centro Nacional de Biotecnología, CNB-CSIC, Darwin 3, Campus de Cantoblanco, 28049 Madrid, Spain.
Marta
M
Nieto
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.
Christopher A
CA
Walsh
D000483:Alleles; D000818:Animals; D000067877:Autism Spectrum Disorder / Q000235:genetics*; D002540:Cerebral Cortex / Q000378:metabolism; D003071:Cognition; D018628:Gene Dosage; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D015894:Genome, Human; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007438:Introns; D051379:Mice; D008822:Mice, Transgenic; D055495:Neurogenesis / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics; D017354:Point Mutation; D040641:Quantitative Trait Loci; D050436:Regulatory Elements, Transcriptional; D012097:Repressor Proteins / Q000235:genetics; D012919:Social Behavior; D014157:Transcription Factors
C080632:CUX1 protein, human; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; D014157:Transcription Factors
ASD; Autism; Brain Evolution; HARs; Human Accelerated regions; noncoding
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