Molecular Evolution: The FOXP2 Protein

Since humans produce vocal sounds far more complex than their closest living relatives, the genes involved should display changes in sequence reflecting this unique trait. The discovery of the first such gene, FOXP2, came about after observing inheritance patterns of a speech disorder within a family simply known as "KE" (an alias to ensure their privacy). The inheritance patterns of this disorder indicated a single autosomal gene was responsible (930, Vargha-Khadem et al). Single gene regulation of a trait as complex as human speech seems unlikely, and more genes must certainly be involved. However, the nature of the gene product of FOXP2 indicates why this gene may have such a large effect on speech.

The FOXP2 protein is a transcription factor, specifically a member of the forkhead class (519, Lai et al). This class of transcription factors regulates genes affecting cell specialization during development of the individual. The KE family contained a single base-pair polymorphism in this gene, compromising the functional structure of the gene product; manifested as defects in processing grammatical syntax and impaired movement of the lower face. Since FOXP2 is the first gene shown to have a direct effect on human speech and language, it allows researchers to begin exploring evolutionary aspects of this trait.

Enard et al compare amino acid sequences of FOXP2 between primate species and mice. This gene contains a region of glutamine repeats, high in interspecial variation, but conserved within each respective species. Aside from this region, the researchers find that the remaining sequence for this gene is among the most highly conserved between humans and rodents (869, Enard et al); only one amino acid change is unique to the mouse lineage, despite 70 million years of separation from primates. However, humans display two distinct amino acid changes from chimpanzees, despite only a few million years of separation. The entire amino acid sequence of this protein is identical between chimpanzees, gorillas and rhesus monkeys; orangutans differ by a single amino acid. At least one change unique to the human lineage seems to affect the function of this protein, allowing a "potential target site for phosphorylation by protein kinase C", indicating at least one possible functional difference in the FOXP2 protein (869, Enard et al). This observation prompted Enard et al to further explore the evolution of this gene in the human lineage.

The researchers eventually attributed these changes to recent positive selection on human FOXP2. Initial analysis revealed an increase in the "ratio of amino-acid replacements over nucleotide changes that do not cause amino acid changes" in the human line, not observed in other primate species (870, Enard). However, this only indicates a change in selection constraints on this gene, not necessarily positive or negative. Sampling human populations from around the globe, they found statistical evidence of positive selection in the unusually high number of rare alleles of this gene; more than expected from a neutrally evolving region. The researchers found further support for positive selective sweep through analysis of recombination rates of FOXP2 introns and surrounding genomic regions; recombination events are fives times more common at FOXP2 intron sites then the average genomic rate. However, their statistical analysis revealed "an extreme skew in the frequency spectrum of allelic variants"towards rare and high-frequency alleles" indicating a positive selective sweep favoring the human-specific changes (871, Enard). Having concluded that the changes to FOXP2 in the human lineage underwent positive selective sweep, Enard et al proceed to estimate when these changes became fixed.

Their analysis of silent changes in this region provided a rough estimate of when these changes first arose. Using a panmictic population of constant size model, they initially estimated "the most likely date since the fixation of the beneficial allele is 0, with approximate 95% confidence intervals of 0 to 120,000 years" (871, Enard et al). Modifying their model to fit with a growing population, they conclude that the fixation occurred within the last 200, 000 years. Since their time estimate coincided with when human populations began appearing around the globe, they concluded that their findings support the notion that language played a major role in ancestral human's rapid spread throughout the world. Enard et al provide convincing support that FOXP2 was involved with the origin of human language, but the specific role it played may be harder to explore.

Since FOXP2 is a transcription factor, this gene most likely affects speech through regulation of other genes. Finding the genes regulated by FOXP2 seems like the next logical step in exploring the role this gene played in human evolution. This could be done by probing the genome with segments of FOXP2 cDNA, and observing chromosome regions binding with these segments. Such exploration could start by observing regions of the human brain damaged after a stroke or physical trauma resulting in impaired speaking; these regions would be excellent candidates to begin probing for FOXP2 activity. However, if there are many more genes involved with speech, especially if unaffected by FOXP2, then its evolution may have not have played as significant a role in human expansion throughout the world as the authors suggest. Animal models could help explore this issue.

Fortunately, some have already begun exploring the role of FOXP2 in other species. Study of songbirds revealed extreme conservation of this gene among birds, but no substitutions resembled those of the human line (Webb et al). Since avian species that vary so greatly in their vocalization abilities show strong conservation of FOXP2, other genes must surely be involved with this trait. This observation seems to indicate that vocal ability relies more on undiscovered genes rather than FOXP2; though FOXP2 may still somehow regulate their expression. However, this can not be thoroughly studied until more genes are found which directly affect vocalization ability. Also, specific study of human FOXP2 function will likely be much more difficult than with animal models.

Ethics constrain the experimental options to explore the role this gene plays in human speech. While the replacement of human FOXP2 with that of a mouse or primate could indicate the effect of this gene product on speech, such an experiment would be enormously controversial. Instead, a study of another family such as KE with polymorphisms in this gene region would be a more ethical way to explore the role of this gene in human language; though location of such a family may be difficult. Alternately, human FOXP2 could be inserted into other mammalian species to observe to effects it has on their normal vocal capabilities. Regardless of the route taken, research ethics can not be ignored when studying any aspect of the human genome, including all future research involving FOXP2.

Enard et al. Molecular Evolution of FOXP2, a gene involved in speech and language. Nature 418, 869-72 (2002).

Lai, C.S. et al. A forkhead-domain gene is mutated in a severe speech and language disorder.Nature 413, 519-523 (2001).

Vargha-Khadem F et al. Praxic and nonverbal cognitive deficits in a large family with a genetically transmitted speech and language disorder. PNAS 92(3), 930-3 (1995).

Webb D.M, Zhang J. FOXP2 in song-learning birds and vocal-learning mammals. Journal of Heredity 96(3), 212-6 (2003).