A humanized NOVA1 splicing factor alters mouse vocal communications

Yoko Tajima (), César D. M. Vargas, Keiichi Ito, Wei Wang, Ji-Dung Luo, Jiawei Xing, Nurdan Kuru, Luiz Carlos Machado, Adam Siepel, Thomas S. Carroll, Erich D. Jarvis and Robert B. Darnell ()
Additional contact information
Yoko Tajima: The Rockefeller University
César D. M. Vargas: The Rockefeller University
Keiichi Ito: The Rockefeller University
Wei Wang: The Rockefeller University
Ji-Dung Luo: The Rockefeller University
Jiawei Xing: Cold Spring Harbor
Nurdan Kuru: Cold Spring Harbor
Luiz Carlos Machado: Cold Spring Harbor
Adam Siepel: Cold Spring Harbor
Thomas S. Carroll: The Rockefeller University
Erich D. Jarvis: The Rockefeller University
Robert B. Darnell: The Rockefeller University

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract NOVA1, a neuronal RNA-binding protein expressed in the central nervous system, is essential for survival in mice and normal development in humans. A single amino acid change (I197V) in NOVA1’s second RNA binding domain is unique to modern humans. To study its physiological effects, we generated mice carrying the human-specific I197V variant (Nova1hu/hu) and analyzed the molecular and behavioral consequences. While the I197V substitution had minimal impact on NOVA1’s RNA binding capacity, it led to specific effects on alternative splicing, and CLIP revealed multiple binding peaks in mouse brain transcripts involved in vocalization. These molecular findings were associated with behavioral differences in vocalization patterns in Nova1hu/hu mice as pups and adults. Our findings suggest that this human-specific NOVA1 substitution may have been part of an ancient evolutionary selective sweep in a common ancestral population of Homo sapiens, possibly contributing to the development of spoken language through differential RNA regulation during brain development.

Date: 2025
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DOI: 10.1038/s41467-025-56579-2

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