A single splice site mutation in human-specific ARHGAP11B causes basal progenitor amplification

Area of Science:

• Evolutionary biology
• Neuroscience
• Genetics

Background:

• The ARHGAP11B gene is crucial for basal progenitor amplification and neocortex expansion in humans.
• ARHGAP11B arose from a partial duplication of ARHGAP11A, encoding a Rho guanosine triphosphatase-activating protein (RhoGAP).
• Human ARHGAP11B mRNA lacks 55 nucleotides, resulting in a truncated RhoGAP domain and a human-specific C-terminus, altering its function.

Purpose of the Study:

• To investigate the molecular mechanism behind the functional divergence of ARHGAP11B.
• To determine the role of the 55-nucleotide deletion and the single nucleotide substitution in ARHGAP11B's function.
• To understand the contribution of ARHGAP11B to human neocortex evolution.

Main Methods:

• Analysis of mRNA splicing mechanisms.
• Reconstruction of ancestral ARHGAP11B complementary DNA (cDNA).
• Assessment of RhoGAP activity and effects on basal progenitor amplification.

Main Results:

• A single C→G substitution creates a novel splice donor site, causing the deletion of 55 nucleotides in ARHGAP11B mRNA.
• Reconstructed ancestral ARHGAP11B exhibits RhoGAP activity.
• Ancestral ARHGAP11B does not increase basal progenitor numbers during neocortex development.

Conclusions:

• A single nucleotide substitution is responsible for the unique properties of human ARHGAP11B.
• These properties, including enhanced basal progenitor amplification, likely drove the evolutionary expansion of the human neocortex.
• The study elucidates a key genetic event in human brain evolution.