Could mice genes reveal the origins of human speech? From Scope, the blog of the Yale Scientific Magazine.
Language is one of the most defining and elusive features of our humanity. “Much of what we know about the origin and the evolution of modern humans, including the acquisition of language ability, remains unexplored,” said Yoko Tajima, a postdoctoral associate at the Rockefeller University.
In a Nature Communications paper, Tajima and Robert Darnell, a professor at Rockefeller University, explored the evolutionary and functional impact of a human-specific gene variant on communication and speech. Their research built upon a 2012 study that compared the DNA of modern humans with Neanderthal and Denisovan fossils, leading to a striking discovery: a single amino acid substitution in the NOVA1 gene that is unique to modern humans. This human-specific variant, known as I197V, occurs when the amino acid isoleucine is swapped out for the amino acid valine at position 197 in the second part of the NOVA1 protein that helps it attach to RNA. In order for a gene to become a protein, it is first transcribed into mRNA. While processing the mRNA transcript, different combinations of coding sequences (exons) can be joined together. This process, called alternative splicing, allows a single gene to produce multiple proteins. NOVA1 is a neuronal RNA-binding protein that regulates that process.
The connection between the NOVA1 protein and speech is apparent. Individuals with a deficiency in one copy of the NOVA1 gene have been observed to exhibit language delays, learning difficulties, and motor and behavioral dysregulation.
The researchers first confirmed that, while the NOVA1 gene is highly conserved across species, the I197V variant was unique to humans and underwent strong positive selection during early Homo sapiens evolution, appearing in all but six of 650,058 human DNA samples analyzed. To investigate the functional consequences of the I197V substitution, the scientists inserted the human-specific I197V variant into mice and compared their molecular and behavioral responses to those of mice carrying the normal NOVA1 gene. While the I197V variant did not affect brain-to-body weight ratio, gene expression levels, or RNA-binding affinity of the protein, it did change alternative splicing. The splicing changes were found across numerous mRNA transcripts, especially those coding for proteins that were binding targets of the protein or implicated in behavior and vocalization. Furthermore, the single amino acid substitution resulted in altered ultrasonic vocalization (USV) in mice pups and increased complexity of courtship communication in adult mice. Specifically, they observed variations in the sound of USV “syllables” in pups who were isolated, as well as more complex high-frequency USVs in adult mice induced by courtship. “Based on these data and observations, we propose that the I197V substitution in NOVA1 may have contributed to the acquisition of language, which is probably a very big advantage for the species to prosper,” Tajima concluded.
Moving forward, the researchers aim to uncover the biological and social significance of the modified courtship vocalizations as well as the molecular mechanisms of NOVA1-mediated RNA regulation. The findings also extend beyond evolutionary biology to potential clinical applications, such as neurorehabilitation for language impairments ranging from developmental disorders in children to neurodegenerative diseases in adults.
Ultimately, the researchers emphasize that human intelligence cannot be attributed to a single gene—let alone a single amino acid change—but believe the implications of the research are no less meaningful. “Our study will constitute one major step forward in a series of many studies that will help us to understand what makes us human,” Darnell said.