A single splice site mutation in human-specific <i>ARHGAP11B</i> causes basal progenitor amplification.

Abstract

The gene <i>ARHGAP11B</i> promotes basal progenitor amplification and is implicated in neocortex expansion. It arose on the human evolutionary lineage by partial duplication of <i>ARHGAP11A</i>, which encodes a Rho guanosine triphosphatase-activating protein (RhoGAP). However, a lack of 55 nucleotides in <i>ARHGAP11B</i> mRNA leads to loss of RhoGAP activity by GAP domain truncation and addition of a human-specific carboxy-terminal amino acid sequence. We show that these 55 nucleotides are deleted by mRNA splicing due to a single C→G substitution that creates a novel splice donor site. We reconstructed an ancestral <i>ARHGAP11B</i> complementary DNA without this substitution. Ancestral ARHGAP11B exhibits RhoGAP activity but has no ability to increase basal progenitors during neocortex development. Hence, a single nucleotide substitution underlies the specific properties of ARHGAP11B that likely contributed to the evolutionary expansion of the human neocortex.