NSF2026: EAGER: The evolution and diversity of the human brain

University Of California-Santa Cruz, Santa Cruz CA

Investigators

Abstract

Human-specific cognitive capacity is evident in many forms. For example, no other species rivals humans’ capacity for speech and language or inter-generational accumulation of knowledge. But what are the genetic underpinnings of human-specific brain evolution and cognition? This project will contrast the genomes of our closest extinct relatives (Neanderthals and Denisovans) with human genomes to identify genetic variants that may play a role in the evolution of human-specific brain. Genomic methods will be used to insert the archaic versions of these genes into human-derived cells. The biology of cells that carry genetic variants that have been extinct for thousands of years will then be studied to help discover recently evolved functions in human brain development and cognition. This project will provide graduate training opportunities in computational genome analysis and experimental genome manipulation. The results of this project have high potential for general public interest as they address fundamental aspects of human uniqueness, and the project may generate opportunities for wide dissemination via public media channels. Further, this project may inform clinical and biomedical research by experimentally describing the functions of genes that work in early brain development. The proposed research enriches the NSF2026 Idea Machine winning entries of 'Harnessing the Human Diversity of Mind' and 'Understanding Scaling of Embodied Cognition.' This project aims to discover and describe functional roles for recently evolved human-specific genetic variants in human-derived cortical organoids. Human-specific variants will be discovered using an innovative computational analysis (a reconstructed ancestral recombination graph) of the genomes of humans and their closest, extinct ancestors – Neanderthals and Denisovans. This approach allows identification of variants that are present in all humans, but absent in the archaic species. Variants present in genes involved in neural development, enriched in this set already, will be prioritized for genetic and functional analysis. Using genome editing of a panel of human-derived iPS cells, this project will re-introduce the extinct archaic variants into various human genetic backgrounds. Each edited iPS line and unedited controls will be assayed for growth, development, and appropriate molecular endophenotypes such as gene expression through stages of cortical organoid induction. Phenotypic deviation from controls may reveal the function roles of the recent genetic innovations in human brain development. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.