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Regulatory logic of human cortex evolution by combinatorial perturbations

Skaros, A.; Vitriolo, A.; Leonardi, O.; Finazzi, V.; Pereira, M. F.; Prazzoli, F.; Trattaro, S.; Moriano, J.; Capocefalo, D.; Villa, C. E.; Boettcher, M.; Boeckx, C.; Testa, G.

2025-05-01 systems biology
10.1101/2025.04.28.651083 bioRxiv
Show abstract

Comparative genomic studies between contemporary and extinct hominins revealed key evolutionary modifications, but their number has hampered a system level investigation of their combined roles in scaffolding modern traits. Through multi-layered integration we selected 15 genes carrying nearly fixed sapiens-specific protein-coding mutations and developed a scalable design of combinatorial CRISPR-Cas9 bidirectional perturbations to uncover their regulatory hierarchy in cortical brain organoids. Interrogating the effects of overexpression and downregulation for all gene pairs in all possible combinations, we defined their impact on transcription and differentiation and reconstructed their regulatory architecture. We uncovered marked cell type-specific effects, including the promotion of alternative fates and the emergence of interneuron populations, alongside a core subnetwork comprising KIF15, NOVA1, RB1CC1 and SPAG5 acting as central regulator across cortical cell types.

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"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.