Ryan N Doan, Byoung-Il Bae, Beatriz Cubelos, Cindy Chang, Amer A Hossain et al.
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.
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, The Homozygosity Mapping Consortium for Autism, Marta Nieto, Christopher A Walsh. Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior. 2016-09-22. https://doi.org/10.1016/j.cell.2016.08.071
A custom episomal plasmid MPRA tested wild-type and mutant versions of 343 biallelic human accelerated region (HAR) mutations in primary neurospheres derived from E14.5 mouse cortex. The packaged table reports the published normalized WT/MT activity ratio and log2 WT/MT effect for each assayed mutation, alongside genomic, population, and regulatory annotations.
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