NEW YORK (GenomeWeb) – A German team has uncovered a splice site mutation suspected of influencing expansion of the human neocortex — the most recently evolved portion of the brain's cerebral cortex, which became enlarged as human-specific cognitive abilities emerged.
As they reported in Science Advances today, the researchers focused on a gene called ARHGAP11B, found to be human-specific based on past comparisons of human, Neanderthal, Denisovan, and non-human primate sequences. Their genomic analyses, coupled with mouse experiments and cell biology assays, suggest that a splice site change — rather than a truncation to the gene itself — lops 55 nucleotides off of the human ARHGAP11B gene transcript relative to the gene's ARHGAP11A orthologue in other vertebrate animals.
That splice site change removes a Rho guanosine triphosphatase (RhoGAP) enzyme-activating portion of the gene, the team explained, contributing to the expansion of a neural progenitor cell type called basal progenitor cells that are implicated in neurocortical development.
"The ability of the ARHGAP11B to amplify [basal progenitors] likely arose more recently from a change that is tiny on a genomic scale but substantial in its functional and evolutionary consequences," senior author Wieland Huttner, a researcher at the Max Planck Institute of Molecular Cell Biology and Genetics, and his co-authors wrote.
The team produced complementary DNA constructs corresponding to an ancestral version of the ARHGAP11B gene before going on to explore the consequences of a cytosine-to-guanine nucleotide change that emerged in humans.
Along with RhoGAP activity assays, localization experiments done with green fluorescent protein-tagged ARHGAP11B, and other cell line experiments, the researchers used developing mouse embryos to tease apart the changes in basal progenitor cell expansion that accompany the characteristic single cytosine-to-guanine mutation found at a splice site in the gene in humans.
Such experiments, paired with findings from past studies and genomic analyses, suggest that basal progenitor cell amplification only occurs in human-specific forms of the ARHGAP11B gene that do not produce proteins capable of performing the Rho-GAP functions found in proteins that result from the ancestral form of the gene.
Based on these findings, the authors argued that "it is not the ARHGAP11 partial gene duplication event [around] 5 million years ago, as such that impacted human neocortex evolution." Rather, they explained, ARHGAP11B's ability to amplify [basal progenitor cells] was likely a more recent change.