Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior

Area of Science:

• Genomics
• Evolutionary Biology
• Neuroscience

Background:

• Human accelerated regions (HARs) are conserved genomic loci showing high divergence in humans, potentially linked to human-specific traits.
• Mutations in HARs regulating social and behavioral traits could impact cognitive and social disorders.

Purpose of the Study:

• To investigate the functional role of HARs in human development and their potential contribution to neurodevelopmental disorders.
• To identify specific HARs and associated genes implicated in autism spectrum disorder (ASD).

Main Methods:

• Whole-genome and targeted "HAR-ome" sequencing to identify rare biallelic point mutations.
• Chromatin interaction sequencing, massively parallel reporter assays (MPRA), and transgenic mice to assess enhancer activity.
• Analysis of mutation frequency in consanguineous individuals with ASD compared to controls.

Main Results:

• A significant excess of rare biallelic HAR mutations was found in individuals with ASD from consanguineous families, suggesting a 5% contribution.
• Disease-linked, biallelic HAR mutations were identified in active enhancers for genes like CUX1, PTBP2, GPC4, and CDKL5.
• These genes are implicated in neural function and/or ASD.

Conclusions:

• Specific HARs are essential for normal neural development.
• Genetic evidence supports the role of HAR mutations in ASD pathogenesis.
• Evolutionary changes in HARs may have influenced human social and cognitive behavior.