title: A single splice site mutation in human-specificARHGAP11Bcauses basal progenitor amplification.
abstract: The geneARHGAP11Bpromotes basal progenitor amplification and is implicated in neocortex expansion. It arose on the human evolutionary lineage by partial duplication ofARHGAP11A, which encodes a Rho guanosine triphosphatase-activating protein (RhoGAP). However, a lack of 55 nucleotides inARHGAP11BmRNA 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 ancestralARHGAP11Bcomplementary 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.
authors.affiliation: Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstraße 108, D-01307 Dresden, Germany.
authors.forename: Marta
authors.initials: M
authors.lastname: Florio
authors.affiliation: Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstraße 108, D-01307 Dresden, Germany.
authors.forename: Takashi
authors.initials: T
authors.lastname: Namba
authors.affiliation: Max Planck Institute for Evolutionary Anthropology, Deutscher Platz 6, D-04103 Leipzig, Germany.
authors.forename: Svante
authors.initials: S
authors.lastname: Pääbo
authors.affiliation: Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstraße 108, D-01307 Dresden, Germany.; Max Planck Institute for the Physics of Complex Systems, Noethnitzer Straße 38, D-01187 Dresden, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Hiller
authors.affiliation: Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstraße 108, D-01307 Dresden, Germany.
authors.forename: Wieland B
authors.initials: WB
authors.lastname: Huttner
mesh_terms: D000818:Animals; D018076:DNA, Complementary / Q000235:genetics; D019143:Evolution, Molecular; D020690:GTPase-Activating Proteins / Q000235:genetics*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D019579:Neocortex; D058953:Neural Stem Cells / Q000166:cytology*; D020033:Protein Isoforms / Q000235:genetics; D012333:RNA, Messenger
chemical_list: C000596803:ARHGAP11A protein, human; C000596802:ARHGAP11B protein, human; D018076:DNA, Complementary; D020690:GTPase-Activating Proteins; D020033:Protein Isoforms; D012333:RNA, Messenger
keywords: ARHGAP11B; RhoGAP; basal progenitors; brain size; gene duplication; human evolution; human-specific gene; neocortex; neocortical expansion; neurogenesis