Single protein may help shape the advent of spoken language

The origin of human language remains mysterious. Are we the only animals that really have complex voices? yes Homo sapiens The only person who can provide detailed instructions to a distant source of freshwater, or the subtle purple and red of a dramatic sunset?

Neanderthals, etc., may have anatomical features in the throat and ears, which may allow the spoken and listening of language to allow us to share variants of genes associated with our ability to speak. However, only in modern humans can we find that enlarged brain regions are essential for language production and understanding.

Now, Rockefeller University researchers have found interesting genetic evidence: protein variants found only in humans may help shape the emergence of spoken language.

In a published study Natural CommunicationsResearchers in the lab of Rockefeller researcher Robert B. Darnell found that when they placed this completely human variant nova1, an RNA-binding protein in the brain, the pair Neurodevelopment is crucial, which is key to mice – it changes their voices to change their voices. each other.

The study also confirms that this variant is not found in Neanderthals or Denisovos, ancient humans, as evidenced by our ancestors as genetic traces in many of today’s human genomes.

“The gene is part of the evolutionary changes in early modern humans and suggests the potential ancient origins of spoken language,” said Darnell, head of the Molecular Neuro-Oncology Laboratory.Nova1 It may be a true human “language gene”, although of course it is only one of many specific genetic changes in humans. ”

Thirty years of production

The anatomical adaptation of the vocal cords and intricate neural networks can enable our language skills. But the genetics behind them are not understood.

A theoretical driving force for genetic language is FOXP2this encoding represents a transcription factor involved in early brain development. People with mutations in this gene exhibit severe phonological defects, including the inability to coordinate lip and oral movements with the sound. In FOXP2, no two amino acid substitutions were found in other primates or mammals, but Neanderthals also had them, suggesting that this variant emerged among the ancestors of two human lineages. But some discoveries FOXP2 It has been controversial and its role in the development of human language is still unclear.

Now Nova1 He has appeared as a candidate. The gene produces a neuron-specific RNA-binding protein for brain development and neuromuscular control, which was first cloned in 1993 and characterized in 1993 with Darnell. It is found in almost the same form on a wide range of biospheres across mammals to birds, but not among birds – humans. Instead, we have our own unique form, characterized by a single change in amino acids, from isoleucine to valin, located in the protein chain 197 (I197V).

I197V is not the only amino acid substitute that distinguishes modern humans from other organisms, pointing to Yoko Tajima, the first author of Darnell’s Lab’s postdoctoral fellow Yoko Tajima. Some of these may be an integral part of brain development. “This change may play an important role in obtaining characteristics that contribute to emergence, expansion and survival Homo sapiens,” she said.

Darnell is an expert in how RNA-binding proteins regulate gene expression, and has been studying Nova1 since the early 1990s, when he and his colleagues first identified it as a trigger for the autoimmune disease of the nervous system, called POMA, which may Causes extreme motor dysfunction. Recently they began to determine the case Nova1 Genetic variation is associated with developing language and motor difficulties.

“Understanding Nova1 is a career endeavor for me,” he said.

The current study led by Tajima uses CRISPR gene editing to replace the common NOVA1 protein found in mice by the human variant I197V. They then used advanced techniques, such as a crosslinked immunoprecipitation (clip) analysis developed by Darnell, to identify the RNA-binding sites of NOVA1 in the midbrain of mice.

Big Reveal

The first noteworthy finding is that human variants have no effect on RNA binding associated with neurodevelopmental or motor control. It operates exactly the same as the replaced operation.

What is that? The second important finding gives them a hint: binding sites that are essentially affected by human variants are located on genes encoding RNAs associated with vocalization.

“In addition, many of the genes associated with sound have also been found to be binding targets for Nova1, further suggesting that Nova1 is involved in vocalization,” Tajima said.

“we would like, Wow. We didn’t expect it. “This is one of the truly surprising moments in science. ”

Darnell’s lab then teamed up with Rockefeller’s linguistic neurogenetics laboratory, led by Erich D. Jarvis, who studied sound learning Molecular and genetic mechanisms.

Changed communication

In the following years, collaborators investigated the effects of vocalization in mice of all ages under different circumstances. They found that the sound patterns of male and female cubs changed.

“All infant mice squeak the mothers ultrasound, and language researchers classify the various squeaks into four “letters” – S, D, U and M,” Darnell noted. “We found that When we ‘transliterated’ the squeaks produced with the human-specific I197V variant, they differ from those of wild-type mice. Some “letters” changed.”

When they studied the hope of mating in male adult mice exposed to female adult mice in Estrus, they found a similar pattern. “They talk differently with female mice,” he said. “People can imagine how this change in voice can have a profound impact on evolution.”

Human Elements

The potential impact of I197V on human evolution became their next focus. To confirm that it was not found among our nearest human relatives – Neanderthals lived primarily in Europe, while Denisovans were named after the Central Asian caves where they were discovered – the researchers will Eight human genomes were compared with three high-coverage Neanderthals and one high-coverage Denisovan genome.

As expected, our ancient relatives (from about 250,000-300,000 years ago that we are thought to divide Nova1 proteins with all non-human animals.

They then combed out 650,058 modern human genomes in the DBSNP database, a short-sequence change catalog from people around the world. If an alternative to I197V exists, find it here.

Of these 650,058 people, all except six have variants of humanity. Those six have ancient variants. Since the samples have been de-identified, the details about them are unknown.

“Our data suggest that the ancestral population of modern African humans evolved the human variant I197V, which then became dominant, perhaps because it gave the advantage associated with voice communication.” “Then, the population left Africa,” he suggested. , spread all over the world.”

Diseases and Diseases

In the future, Darnell’s lab will study how Nova1 regulates language function with language or developmental disorders.

“We believe that understanding these issues will provide important insights into how the brain operates during the transmission of sounds and how its misregulation leads to certain diseases,” Tajima said.

For example, its neural path may work when various diseases cause people who cannot speak. Perhaps it affects the development of nonverbal autism; NOVA1 is one of many genes associated with autism spectrum disorder. In 2023, the lab reported patients with Nova1 haplopathy, whose neurological symptoms include speech delay.

“Our findings may be clinically significant in many ways, from developmental disorders to neurodegenerative diseases,” Darnell added.