Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Animals
  • Autism Spectrum Disorder / genetics*
  • Cerebral Cortex / metabolism
  • Cognition*
  • Gene Dosage
  • Genetic Predisposition to Disease*
  • Genetic Variation
  • Genome, Human
  • Homeodomain Proteins / genetics
  • Humans
  • Introns
  • Mice
  • Mice, Transgenic
  • Neurogenesis / genetics*
  • Nuclear Proteins / genetics
  • Point Mutation*
  • Quantitative Trait Loci
  • Regulatory Elements, Transcriptional
  • Repressor Proteins / genetics
  • Social Behavior*
  • Transcription Factors

Substances

  • CUX1 protein, human
  • Homeodomain Proteins
  • Nuclear Proteins
  • Repressor Proteins
  • Transcription Factors