Unraveling mechanisms of human brain evolution

Abstract

Evolutionary changes in human brain structure and function have enabled our specialized cognitive abilities. How these changes have come about genetically and functionally has remained an open question. However, new methods are providing a wealth of information about the genetic, epigenetic, and transcriptomic differences that set the human brain apart. Combined with in vitro models that allow access to developing brain tissue and the cells of our closest living relatives, the puzzle pieces are now coming together to yield a much more complete picture of what is actually unique about the human brain. The challenge now will be linking these observations and making the jump from correlation to causation. However, elegant genetic manipulations are now possible and, when combined with model systems such as organoids, will uncover a mechanistic understanding of how evolutionary changes at the genetic level have led to key differences in development and function that enable human cognition.

Keywords: brain; development; evolution; human evolution; neuroscience; organoids.

Figure 1. Evolution of the brain

Phylogenetic tree (branch lengths not to scale) of selected major metazoan phyla with nervous systems, illustrating key evolutionary innovations and illustrations of representative organisms: Hydra (cnidaria), octopus (mollusk), Drosophila (arthropoda), tunicate larva (tunicata), mouse (rodent), and human (primate). Illustrations shown below of differences in neurogenesis in arthropods (left) compared with chordates (right). Also shown are illustrations of a cross-section of the gray matter of mouse and human cortex, based on the data from Beaulieu-Laroche et al., showing the six layers. Mouse and human brain, as well as cross-sections, are shown to scale.

Figure 2. Evolution of human-specific brain features

Phylogenetic tree (branches not to scale) of the hominoids, including ancient hominin relatives and the great apes. Shown below selected species are illustrations of brain and skull shape, cranial capacity (cc, cubic centimeters), and encephalization quotient (EQ). H. habilis, H. erectus, and H. neanderthalensis morphology data from Bruner and Beaudet, present-day and ancient human morphology data from Neubauer et al., and chimpanzee morphology data from Gómez-Robles et al. EQ and volume data from Williams, DeSilva et al., and VanSickle et al. Below the human and chimpanzee are shown illustrations of the cortical thickness and layering of cortical area VP, based on data from de Sousa et al., with the average of the relative proportions of layers in cortical areas V2 and VP.

Figure 3. Potential human-specific mechanisms

(A) Illustration of human-specific developmental differences. Early neuroepithelium gives rise to neural crest, which contributes to facial structures, while retained neuroepithelium gives rise to the brain. The telencephalon is particularly expanded, with increased proliferative capacity of the neuroepithelium, shown in a magnified view, due to delayed transition to radial glia. Radial glia and basal progenitors, including outer or basal radial glia, are highly proliferative in humans. The transition to astrogliogenesis, represented by orange astrocytes, is delayed, as is the maturation of neurons. A unique subtype of microglia expressing FOXP2 is represented by the green cell at the right. Key identified genes and their developmental contexts are also shown. (B) Illustration of the difference between neoteny and bradychrony. Neoteny was originally coined in reference to the axolotl, which retains juvenile features in adulthood. Below is shown the result of hypothetical neuronal neoteny, which would similarly result in juvenile neurons. Instead, bradychrony results in mature neurons in adulthood, but because the process is slower, the result is increased complexity.

Figure 4. Unraveling mechanism

Comparative studies reveal species-specific phenotypic differences, such as brain size and neuronal morphology, which can be correlated with genetic differences. Shown are a few representative human-specific genetic differences correlated with neurodevelopmental differences. A region of chromosome 1q21 is shown, revealing the large number of novel human genes. HARs at the FZD8 and CUX1 loci are also shown as examples. Below are the homologous chimpanzee loci with the ancestral NOTCH2NL duplication resulting in a nonfunctional product (denoted by *). Functional studies, such as overexpression or knockout in model systems provide strong support linking genetics to phenotype. In the future, refined genetic manipulation of model systems, such as organoids or mice, to mimic the evolutionary changes will reveal whether and how human-specific changes have enabled differences in brain development to give rise to the large and complex human brain.