Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior

Ryan N. Doan, Byoung Il Bae, Beatriz Cubelos, Cindy Chang, Amer A. Hossain, Samira Al-Saad, Nahit M. Mukaddes, Ozgur Oner, Muna Al-Saffar, Soher Balkhy, Generoso G. Gascon, Marta Nieto, Christopher A. Walsh

Research output: Contribution to journalArticlepeer-review

195 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)341-354.e12
JournalCell
Volume167
Issue number2
DOIs
Publication statusPublished - Oct 6 2016

Keywords

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

ASJC Scopus subject areas

  • General Biochemistry,Genetics and Molecular Biology

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