ARHGAP11B arose by a partial duplication of
ARHGAP11A around 5 mya
[1][2][3][4][37,38,39,40].
ARHGAP11A is a ubiquitous gene that is composed of 12 exons and encodes a RhoGAP (Rho GTPase Activating Protein) domain-containing protein
[5][6][41,42]. The partial duplication of
ARHGAP11A resulting in
ARHGAP11B encompassed only the first 8 exons of
ARHGAP11A [7][43]. This truncated copy of
ARHGAP11A (referred to as ancestral
ARHGAP11B) most likely did not contribute to cortical expansion. Indeed, a functional analysis of ancestral
ARHGAP11B showed that it lacked the ability to promote BP proliferation
[7][43]. Although the
ARHGAP11B gene is only a truncated copy of
ARHGAP11A, it contains the full nucleotide sequence of the RhoGAP domain. However, at the protein level, ARHGAP11B features only a truncated RhoGAP domain, lacking the last (C-terminal) 26 amino acids of this domain
[7][43]. In line with this finding, functional analyses showed that ARHGAP11B lacks RhoGAP activity in vivo
[8][7][22,43]. The truncation of the RhoGAP domain, despite the presence of the full nucleotide sequence for this domain in the
ARHGAP11B gene, is due to a single C → G nucleotide substitution in the
ARHGAP11B gene, which most likely occurred after the partial gene duplication event. This substitution generated a novel splice donor site in
ARHGAP11B, leading to the loss of 55 nucleotides upon
ARHGAP11B mRNA splicing. This loss led to a frameshift that resulted in a novel, human-specific 47 amino acid-long C-terminal sequence of ARHGAP11B
[7][43]. In contrast to the ancestral
ARHGAP11B gene that lacks the C → G nucleotide substitution and that would encode an ARHGAP11B protein containing a complete RhoGAP domain and exhibiting RhoGAP activity in vivo, the
ARHGAP11B gene carrying this substitution, and the truncated RhoGAP domain-containing protein generated from it that can promote BP proliferation (see below), have often been referred to as modern
ARHGAP11B/ARHGAP11B
[7][43]. For the sake of simplicity, the latter will from now on be referred to merely as “
ARHGAP11B/ARHGAP11B”.