ARHGAP11B is a human-specific gene that plays a significant role in the development and expansion of the human brain, particularly the neocortex. This region of the brain is associated with higher cognitive functions such as reasoning and language. Research indicates a strong connection between ARHGAP11B and the increased size and folding of the human neocortex. The gene’s presence is unique to humans and closely related extinct hominins, suggesting its involvement in the evolutionary changes that led to the distinct human brain.
The Evolutionary Origins of ARHGAP11B
The ARHGAP11B gene emerged through a partial duplication of an ancestral gene called ARHGAP11A. This evolutionary event is estimated to have occurred approximately five million years ago, specifically along the lineage that diverged from chimpanzees and led to modern humans, Neanderthals, and Denisovans. The original ARHGAP11A gene is widespread across various species, but the duplicated version, ARHGAP11B, underwent a specific genetic change that altered its function.
A single point mutation, a C-G transversion, occurred within the duplicated gene sequence. This alteration led to a significant change in the protein produced by ARHGAP11B, resulting in a novel sequence of 47 amino acids that is specific to this human gene. This new protein sequence conferred a “gain of function,” meaning it acquired new capabilities not present in the original ARHGAP11A gene.
ARHGAP11B is exclusive to modern humans and our extinct relatives, Neanderthals and Denisovans. It is not found in other primate species, including chimpanzees. This restricted distribution highlights its contribution to the unique brain characteristics distinguishing humans from other primates.
The emergence of ARHGAP11B represents a rare instance of a gene arising directly on the human lineage. This genetic innovation shows how specific genetic changes can drive evolutionary adaptations, contributing to the expansion of the human brain. Its unique origin points to its specific involvement in human cognitive development.
ARHGAP11B’s Function in Brain Development
ARHGAP11B primarily influences brain development by promoting the proliferation of neural stem cells, particularly a type known as basal radial glia cells (bRGCs), within the developing neocortex. These cells are precursors to neurons and are especially abundant in the outer subventricular zone of the human fetal brain. The gene’s activity extends the period during which these stem cells divide and multiply, rather than differentiating into mature neurons.
By prolonging the proliferative phase of bRGCs, ARHGAP11B increases the total number of neurons generated during brain development. This expanded pool of neurons leads to the larger size of the human neocortex compared to other primates. The gene also plays a role in the extensive folding, or gyrification, of the human neocortex, which allows for a greater surface area.
Experimental evidence supports the role of ARHGAP11B in brain expansion. Studies involving the expression of human ARHGAP11B in model organisms like mice and ferrets have shown notable effects. For instance, when ARHGAP11B was expressed in embryonic mouse neocortex, it led to an increased number of basal progenitors and an enlargement of the cortical plate area, even inducing some folding in the normally unfolded mouse neocortex. Similarly, expressing ARHGAP11B in marmoset fetuses resulted in an enlarged neocortex.
Further research using brain organoids, which are laboratory-grown three-dimensional cell structures mimicking brain development, has provided additional insights. Introducing ARHGAP11B into chimpanzee brain organoids doubled the levels of basal progenitors, bringing them closer to human levels. Conversely, when ARHGAP11B was removed or its function inhibited in human brain organoids, the number of basal progenitors decreased to levels comparable to those found in chimpanzees. These findings demonstrate that ARHGAP11B is both necessary and sufficient for maintaining the elevated levels of basal progenitors characteristic of the human fetal neocortex.
The gene’s influence on specific neural stem cell populations, particularly bRGCs, shows how a single gene can impact brain architecture. This increased neuron production, especially of upper-layer neurons associated with complex cognitive functions, results from ARHGAP11B’s action. The overall effect is a larger, more complex neocortex.
ARHGAP11B and Neurological Research
Studying ARHGAP11B offers insights into the evolutionary processes that shaped the human brain and its cognitive capabilities. Understanding how this gene contributes to neocortex expansion helps researchers appreciate the genetic basis of human intelligence and behavior. The gene links our genetic heritage to the development of complex cognitive functions.
Beyond its evolutionary context, ARHGAP11B is also investigated for its role in neurodevelopmental disorders. Conditions involving abnormalities in brain size or cortical development, such as microcephaly or macrocephaly, might be linked to variations or dysfunctions in this gene. ARHGAP11B provides a model system for exploring how genetic factors influence neuronal proliferation and differentiation, which dictates brain structure.
Ongoing research into ARHGAP11B also positions it as a research tool for understanding neuronal proliferation and survival. Scientists use this gene to explore how neural stem cells divide and mature, which could have implications for regenerative medicine or brain repair. This research provides a deeper understanding of brain biology.