Autism risk genes are evolutionarily ancient and maintain a unique feature landscape that echoes their function

Area of Science:

• Genomics
• Evolutionary Biology
• Neuroscience

Background:

• Autism risk (ASD), developmental regulatory (DevReg), and central nervous system (CNS) genes are hypothesized to possess distinct genomic features.
• Previous research suggests these genes are large, enriched in repeats, and mutation-intolerant, but the functional relevance remains unclear.

Purpose of the Study:

• To investigate the genomic feature landscape of ASD, DevReg, and CNS genes.
• To understand the functional, developmental, and evolutionary implications of these features.

Main Methods:

• Compiled ASD, DevReg, CNS, housekeeping, and whole genome control (WGC) gene groups.
• Extracted gene features including size, repeat content, transcript variants, and variation intolerance (pLI scores, CNV data).
• Estimated gene age and protein-protein interaction (PPI) networks.

Main Results:

• ASD, DevReg, and CNS genes are significantly longer, produce larger proteins, and have more conserved noncoding elements and transposable elements compared to WGC.
• These gene groups exhibit higher variation intolerance.
• Even after controlling for gene size and mutation tolerance, ASD genes retain unique features, with highly mutation-intolerant ASD genes showing larger PPI networks.

Conclusions:

• ASD, DevReg, and CNS genes share ancient origins and distinct genomic characteristics related to their age and function.
• These features contribute to their regulatory complexity and network interactions.
• Findings support current autism genetics research and enhance understanding of gene evolution and function.