Genomic divergence and brain evolution: How regulatory DNA influences development of the cerebral cortex

Abstract

The cerebral cortex controls our most distinguishing higher cognitive functions. Human-specific gene expression differences are abundant in the cerebral cortex, yet we have only begun to understand how these variations impact brain function. This review discusses the current evidence linking non-coding regulatory DNA changes, including enhancers, with neocortical evolution. Functional interrogation using animal models reveals converging roles for our genome in key aspects of cortical development including progenitor cell cycle and neuronal signaling. New technologies, including iPS cells and organoids, offer potential alternatives to modeling evolutionary modifications in a relevant species context. Several diseases rooted in the cerebral cortex uniquely manifest in humans compared to other primates, thus highlighting the importance of understanding human brain differences. Future studies of regulatory loci, including those implicated in disease, will collectively help elucidate key cellular and genetic mechanisms underlying our distinguishing cognitive traits.

Keywords: corticogenesis; enhancer; evolution; neocortex; stem cell.

Figure 1

Overview of cortical neurogenesis in mice and humans. A: Cartoon representation of the embryonic mouse neocortex with a whole mount view (top left); 1/2 coronal section (bottom left) and high magnification view (right, boxed region from left). B: Simplified cartoon representation of neocortical section from human. For both A and B, the major cell populations and primary cortical layers are indicated. Major progenitors include: radial glial cell (orange, RGC); intermediate progenitor (green, IP); and outer radial glia/basal radial glia (red, oRG/bRG). RGCs undergo symmetric divisions to self-renew (shown as a half circle arrow). RGCs also undergo asymmetric divisions to generate new RGCs, IPs, and neurons (blue). Humans and other nonhuman primate neocortices contain abundant oRG/bRGs. In addition to RGCs, oRGs and IPs also produce neurons, as indicated by arrows. Major cortical layers of the mouse include cortical plate (CP), intermediate zone (IZ), sub-ventricular zone (SVZ), and ventricular zone (VZ). Major cortical layers of primate brains, including humans include the VZ, CP, IZ/sub-plate (IZ/SP). Primates also contain an expanded basal ventricular zone called the outer sub-ventricular zone (OSVZ) as well as an inner sub-ventricular zone (ISVZ). The mouse is shown for comparison with human as many functional studies have been performed in mice.

Figure 2

An example of a human-accelerated enhancer influencing corticogenesis. A: A mock example of a human-accelerated locus showing extremely high evolutionary conservation up until the Homo sapiens divergence, when there is rapid accumulation of changes. B: E10.0 mouse transgenic embryos depicting β-galactosidase enhancer activity (blue) driven by either chimpanzee or human HARE5. Hs-HARE5 has stronger enhancer activity in the developing neocortex. C: E18.5 mouse brains from indicated genotypes, with dotted line drawn from WT (control) overlaid on other two genotypes. Hs-HARE5 activation of Fzd8 induces larger embryonic brains with more Foxp1-positive neurons. This phenotype was evident in multiple independent transgenic lines. D: A schematic model for how HARE5 may influence human brain size, by promoting expansion of neural progenitors that eventually leads to production of more neurons and a larger brain. Panel B is reproduced from [59] with permission form Elsevier Publishing.