Tangled web. The network of genes that work in concert with both the chimp and human FOXP2 is complex. Large green hubs are the most important genes; lines that connect two genes indicate whether their expression goes up (red) o

G. Konopka et al., Nature 462 (12 November 2009); (Inset) Tom Brakefield/Stockbyte

What's Behind Our Gift of Gab?

For the first time, scientists have compared a vast network of human genes responsible for speech and language with an analogous network in chimpanzees. The findings help shed light on how we moved beyond hoots and grunts to develop vast vocabularies, syntax, and grammar.

The centerpiece of the study is FOXP2, a so-called transcription factor that turns other genes on and off. The gene rose to fame in 2001 when researchers showed that a mutant form of it caused an inherited speech and language problem in three generations of the "KE family" in England. The following year, researchers showed that normal FOXP2 differed by only two amino acids--the building blocks of proteins--between humans and chimpanzees. Analyzing more ancestral species, they further showed that the gene was highly conserved all the way up to chimps, suggesting that it played a prominent role in our unique ability to communicate complex thoughts.

Genes rarely act alone, however, so a team led by neurogeneticist Daniel Geschwind of the University of California, Los Angeles, decided to suss out FOXP2's partners. Geschwind, Genevieve Konopka, who is one of his postdocs, and colleagues first inserted the human and chimp versions of FOXP2 into cells derived from human neurons. In all, they identified 116 genes that were turned on or off differently by human FOXP2 versus chimp FOXP2. The researchers found similar results in brain tissue from both species, they report tomorrow in Nature. The data allowed the team to make complex maps of FOXP2's vast genetic network that revealed other critical interactions (see diagram). "These genes become outstanding candidates for being part of the language circuit," says Geschwind.

Among the interesting genes that stood out were ones linked to craniofacial formation and development of the central nervous system. Mutant forms of some of these genes are also known to cause motor-related speech defects and mental retardation.

Faraneh Vargha-Khadem, a cognitive neuroscientist at the Institute of Child Health in London who has studied the KE family for more than 20 years, says the new genetic data nicely fit with her own observations about the mutant FOXP2 disorder. "It's very consistent with what we proposed, and it's exciting to have this evidence," she says. As her work has shown, orofacial problems in the KE family members are strongly related to their cognitive difficulties with speech and language. So the mind and the mechanics are intimately linked. "It makes sense these two things have to work together," she says.

The findings, however, do not mesh well with work from some other leaders in the field. Simon Fisher, a geneticist at Oxford University's Wellcome Trust Centre for Human Genetics whose lab discovered the KE family's FOXP2 mutation, reported last year that FOXP2 turned down CNTNAP2, which in turn had a significant link to a language impairment that compromises a person's ability to use and understand words. But CNTNAP2 did not appear to be regulated by FOXP2 in the Geschwind lab's new analysis. Both Fisher and Geschwind say the discrepancy may have to do with the different cell lines and assays used in the two studies.

In another cautionary note, geneticist Wolfgang Enard of the Max Planck Institute of Evolutionary Anthropology in Leipzig, Germany, who helped discover the difference between human and chimp FOXP2 and has developed a related mouse model, says he so far has failed to find similar chimp-human differences in gene regulation in his own lab. He says it is now critical to repeat the study with more neuronal cell lines. "If the findings are right," he says, "the impact would be enormous."