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Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior.

Cell | 2016

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.

Pubmed ID: 27667684 RIS Download

Mesh terms: Alleles | Animals | Autism Spectrum Disorder | Cerebral Cortex | Cognition | Gene Dosage | Genetic Predisposition to Disease | Genetic Variation | Genome, Human | Homeodomain Proteins | Humans | Introns | Mice | Mice, Transgenic | Neurogenesis | Nuclear Proteins | Point Mutation | Quantitative Trait Loci | Regulatory Elements, Transcriptional | Repressor Proteins | Social Behavior

Associated grants

  • Agency: NCRR NIH HHS, United States
    Id: S10 RR028832
  • Agency: NIMH NIH HHS, United States
    Id: U24 MH081810
  • Agency: NIMH NIH HHS, United States
    Id: R01 MH083565
  • Agency: NIMH NIH HHS, United States
    Id: RC2 MH089952
  • Agency: Howard Hughes Medical Institute, United States
  • Agency: NINDS NIH HHS, United States
    Id: R21 NS091865
  • Agency: NINDS NIH HHS, United States
    Id: T32 NS007484

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MutationTaster (tool)


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