Human brains are roughly three times larger than those of our closest living relatives, the chimpanzees, and this project aims to find out which specific genetic changes caused that expansion. The neocortex—the brain region behind higher cognition—is enlarged in humans, but the evolutionary mechanisms remain unknown. One leading idea is neoteny: a delay in brain development that allows more neurons to be produced. This project will test that idea directly. The researchers will grow miniature brain organoids from human and nonhuman ape cells, then use multi-omics techniques to compare epigenetic and metabolic signatures in neural progenitors. They will also examine signals from the choroid plexus, a brain tissue that develops differently in humans. Finally, they will swap genetic loci between species to see if human-specific changes causally increase neuron production. This is fundamental science. It will not produce a drug or a diagnostic. But understanding how human brain size evolved could eventually illuminate what goes wrong in neurodevelopmental disorders where brain growth is disrupted, such as microcephaly. More broadly, it reveals how a handful of genetic changes can reshape an entire organ—a question that touches every branch of developmental biology.
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The human brain is greatly enlarged compared with other mammals and even our closest living relatives, the other great apes. The neocortex is thought to contribute to higher cognitive capabilities, and as such its enlargement is likely a major contributor to our success as a species. However, the evolutionary mechanisms responsible for this enlargement are still unclear. In particular, which of the many human-specific genetic changes are responsible for expansion of the cerebral cortex are unknown. Increasing evidence points to a delay in development, or neoteny, as being important for enabling increased neuron production and size, yet how that delay comes about is also not known. In this proposal, we will use human and nonhuman ape cerebral organoids to examine this question and to uncover which genetic loci and developmental signalling processes have been key to human-specific cortical size determination. We will use a combination of multi-omics approaches to probe the epigenetic and metabolic signatures of cortical progenitors at various stages, to reveal key regulators of neural fate and identify human-specific changes that allow for delayed differentiation and thus protracted progenitor expansion. We will also investigate extrinsic, cerebrospinal fluid derived signals secreted by the choroid plexus, a brain tissue exhibiting key developmental differences in the human fetal brain. Finally, pharmacological and genetic perturbations, including cross-species genetic locus swapping experiments, will functionally test whether the identified regulators and their relevant human-specific genetic changes have a causal role in progenitor and neuron expansion. This combination of state-of-the-art organoid, omics, and genetic engineering approaches will reveal not only which factors regulate timing and cell fate, but also which evolutionary genetic changes are responsible for human brain expansion.
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