Elizabeth Anne Werren

Humans have exceptionally large brains relative to their body size, with a remarkable enrichment of neurons in the cerebral cortex. Extensive efforts in anthropology have focused on delineating the adaptive pressures that led to these changes during our evolution. However, the genetics underlying human cortical expansion, favored by natural selection, have not been well-explored. This proposal aims to experimentally test hypotheses about human biological origins by investigating the impact of human-specific genomic variants on the development of the human cerebral cortex’in terms of neuronal density and cellular composition’as well as establish a functional model for studying brain evolution.

Human and chimpanzee in vitro brain organoids’3D structures differentiated from stem cells that mimic in vivo brains’provide an unprecedented opportunity to generate functional data on how human-specific genetic changes shape the developing brain. A two-step strategy will be used to investigate the genetics of human cortical expansion: 1) gene editing to evaluate the effect of disrupted human-specific sequence in human organoids, and 2) genetic introduction of human-specific sequences into chimpanzee organoids to measure the effect on neural development. I predict to see effects on neural progenitor cell kinetics, findings that will advance our understanding of the molecular evolution of the human brain.