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Differences in Speech Gene Deciphered in Humans and Chimps


Investigators reported that many of the genes that are regulated by the human version of mutant FOXP2—the first mutation tied to speech and language problems — are involved in neurodevelopment.

Almost a decade ago, British researchers identified a mutation in three generations of a family with verbal dyspraxia. Many of the family members share major problems mastering complex sequences of mouth and face movement that are critical to human speech. They also have problems expressing their thoughts and comprehending spoken and written language.

This was the first mutation tied to speech and language problems and others have gone on to show that the gene, which makes a transcription factor called FOXP2 (forkhead box protein P2), evolved with two new amino acids by the time it shows up in humans. Chimps do not share this new change.


FOXP2 mutations have been identified in other families with speech and language problems. Wikipedia Commons

In a new study, Daniel H. Geschwind, MD, the Gordon and Virginia MacDonald Distinguished Chair in Human Genetics and professor of neurology and psychiatry at the University of California Los Angeles School of Medicine, and colleagues at the Yerkes National Primate Research Center and Emory University School of Medicine studied gene expression in cells carrying either chimp or human versions of the FOXP2 gene and discovered that these two amino acid changes did lead to differential transcriptional regulation, at least in a culture dish. When they looked at gene expression in brain tissue from humans and chimps they also found significant differences, especially in genes involved in brain development and disease.


DR. DANIEL H. GESCHWIND and colleagues found that some of the FOXP2 genes had been linked to cerebellar motor function, craniofacial formation, and cartilage and connective tissue formation — all important in laying down the neural circuitry and the physical structures of the face and jaw “that are needed for spoken language.”

“These targets may have a critical function in the development and evolution of language circuitry in humans,” said Dr. Geschwind. But FOXP2 is just one of the many likely genes that influence human speech and language.

In the study, published Nov. 12 in Nature, the authors carried out whole-genome microarray screens of cells engineered to express chimp or human FOXP2 and found that, compared to the chimps, 61 genes were significantly up-regulated and 55 genes down-regulated in the human cells. They said that the changes “are an indication of differential transcriptional regulation by these two proteins.” FOXP2 is a transcription factor that turns other genes down.


In 2002, Svante Paabo, PhD, and his group at the Max Planck Institute for Evolutionary Anthropology in Germany provided the first evidence that FOXP2 underwent “accelerated evolution” in human lineage, although this has not been without controversy.

Dr. Paabo and colleagues found that the human and chimpanzee versions of the protein had acquired two amino acid changes in the lineage that led to modern humans. There was also evidence that the gene had been subject to Darwinian selection, the theory that there is a selective pressure that favors positive change.

According to Simon Fisher, DPhil, a geneticist at the Wellcome Trust Centre for Human Genetics and one of the scientists who identified mutant FOXP2 in the multigenerational family with speech and language problems, the finding “triggered a great deal of speculation over whether the differences in human and chimpanzee versions of FOXP2 might have some relationship with the emergence of speech and language in our species.”

The new work by Dr. Geschwind and colleagues provides evidence that this evolutionary event may be a key that unlocks the door to understanding how humans learned to speak and understand language. They validated the findings in tissue samples and have begun to map out the downstream pathways that are affected by this evolutionary change.

Dr. Geschwind's team reported that many of the genes that are regulated by the human version of FOXP2 are involved in neurodevelopment. The team said that some of the genes had been linked to cerebellar motor function, craniofacial formation, and cartilage and connective tissue formation — all important in laying down the neural circuitry and the physical structures of the face and jaw “that are needed for spoken language,” they wrote in the Nature paper.

Dr. Geschwind said that the observed differences suggest that “this FOXP2 mhuman gene is selected for and related to language. Many of the genes are expressed in the frontal lobe and in the striatum, regions of the brain that controls cognition and higher order functions. “Some of the targets are also under positive selection in the human lineage,” he said.

Dr. Fisher said the finding is an important step forward. “Scientists can move closer to a functional understanding of the roles of FOXP2 in the neural bases of human speech and language.”

Finding the FOXP2 Gene

The FOXP2 finding builds on the British family mutation published in 2001 by scientists at the Wellcome Trust Centre for Human Genetics in Oxford. The KE family was discovered in the early 1990s by researchers at the Institute of Child Health in London. In this three-generation family half of its members had severe language and speech problems. The Institute of Child Health team approached the Oxford researchers and asked them to help identify any genetic mutations shared by the affected family members.

“Based on the inheritance pattern observed through the generations, it was suspected that their problems could be explained by damage to only one copy of just a single gene,” said Simon Fisher, DPhil, a geneticist at the Wellcome Trust Centre for Human Genetics and one of the scientists who identified mutant FOXP2. “By directly studying the DNA of people in the KE family, we were able to confirm this. By 1998, we pinpointed a section on chromosome 7 where we believed the mutated gene must lie. A few years later, in 2001, we discovered the human FOXP2 gene in this section of chromosome, and showed that all the affected KE family members carried a mutation (inherited from the grandmother), disturbing a crucial part of this gene.”

They have since identified other FOXP2 mutations in other families with similar speech and language problems. “This remains the only example where damage to a single gene is sufficient to derail speech and language skills, while leaving other faculties relatively spared,” said Dr. Fisher. He emphasized that they do not consider it as a gene for speech or language but one that plays a role in the neural basis of such activities.

The British researchers have gone on to show that the KE mutation damages the function of the FOXP2 protein, preventing it from binding to the DNA of the genes it normally regulates. The affected KE family members have reduced amounts of functional FOXP2 protein; this seems to be a problem for the ways that certain brain circuits develop and function, although the other tissues where FOXP2 is switched on seem to cope fine with a reduced amount, Dr. Fisher explained. Similarly, other families with FOXP2 mutations are also thought to produce “broken” versions of the protein. which impair brain development and function.

Dr. Fisher and his colleagues are using animal models to characterize the effects of the KE family mutation. They generated mice with the equivalent mutation to the one that disrupts human FOXP2 in the KE family. Mice that carried one normal copy and one mutant copy of the gene (matching the situation for the affected humans) showed overtly normal development. However, these mice displayed deficits when learning to make rapid coordinated sequences of movements, said Dr. Fisher.

“We examined the brain circuits where the gene is normally switched on, which are already suspected to be important for this kind of learning,” he said. “We uncovered abnormalities in the way that the connections between nerve cells are strengthened or weakened (synaptic plasticity) in these circuits. We suspect that the functions of human FOXP2 in spoken language are built on these ancient functions in affecting plasticity of brain circuits that help sequence movements.”

The British investigators have also been using functional genomics to search for genes that FOXP2 regulates in brain cells. In 2008 they identified CNTNAP2, a neurexin superfamily gene, as a novel target, which was interesting as Dr. Geschwind's group found this gene to be associated with language delay in autism.

When Dr. Fisher's team tested CNTNAP2 gene variants in children with typical forms of language impairment, they identified a cluster of variants that were significantly associated with poor language performance. This work was the first to show that pathways downstream of FOXP2 can be broadly involved in common language problems, Dr. Fisher said.


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