View Full Version : FOXP2: Not so Central to Human evolution?

08-08-2012, 02:21 PM
Limited access article by Dr. Todd Preuss, April 25, 2012: http://www.pnas.org/content/109/suppl.1/10709.full?sid=b327f37a-6c29-4322-b44d-03d3a736a37d

Human brain evolution: From gene discovery to phenotype discovery


The rise of comparative genomics and related technologies has added important new dimensions to the study of human evolution. Our knowledge of the genes that underwent expression changes or were targets of positive selection in human evolution is rapidly increasing, as is our knowledge of gene duplications, translocations, and deletions. It is now clear that the genetic differences between humans and chimpanzees are far more extensive than previously thought; their genomes are not 98% or 99% identical. Despite the rapid growth in our understanding of the evolution of the human genome, our understanding of the relationship between genetic changes and phenotypic changes is tenuous. This is true even for the most intensively studied gene, FOXP2, which underwent positive selection in the human terminal lineage and is thought to have played an important role in the evolution of human speech and language. In part, the difficulty of connecting genes to phenotypes reflects our generally poor knowledge of human phenotypic specializations, as well as the difficulty of interpreting the consequences of genetic changes in species that are not amenable to invasive research. On the positive side, investigations of FOXP2, along with genomewide surveys of gene-expression changes and selection-driven sequence changes, offer the opportunity for “phenotype discovery,” providing clues to human phenotypic specializations that were previously unsuspected. What is more, at least some of the specializations that have been proposed are amenable to testing with noninvasive experimental techniques appropriate for the study of humans and apes.

Why we think FOXP2 is important:

FOXP2 in Human Evolution.

If language is a human specialization, and FOXP2 plays an important role in the development of speech and language, it is natural to ask whether FOXP2 underwent evolutionary changes in its sequence or expression patterns in human evolution. Enard et al. (67) addressed this question, and found that, although the FOXP2 protein sequence is very strongly conserved in mammalian evolution generally, human FOXP2 differs by two amino acids from that of chimpanzees, gorillas, and macaques, all of which have identical sequences. Both substitutions are in exon 7: a threonine-to-asparagine substitution at position 303 (T303N) and an asparagine-to-serine substitution at position 325 (N325S); the latter substitution creates a potential phosphorylation site. The occurrence of two amino acid fixations is highly unlikely to have occurred by chance, so it is reasonable to conclude that these changes were the result of positive selection, a conclusion supported by analysis of variation in intronic regions of the gene. [Interestingly, at approximately the same time, two other groups independently reported that FOXP2 is among the genes likely to have undergone positive selection in human evolution, based on the ratio of nonsynonymous to synonymous nucleotide changes (Ka/Ks) in genes for which sequence information was available for humans, chimpanzees, and other species (45, 68).] Enard et al. (67) argued that the data are consistent with a selective sweep resulting in fixation of the two human-specific amino acid changes within the past 200,000 y, and speculated that this event occurred coincident with or subsequent to the appearance of modern Homo sapiens and is related to the ability to produce the orofacial movements required for speech.

Why we may be overstating its importance:

Connecting Genes and Phenotypes

As a gene associated with a human-specific trait, FOXP2 would at first glance seem to be a dream come true for evolutionary geneticists. Moreover, it is hard not to be impressed by the depth and breadth of the research related to FOXP2. Nevertheless, there is still no clear or direct connection between the human-specific amino acid substitutions in FOXP2 and speech or language—not from the comparative studies, nor from the mouse-model studies, nor from the gene expression studies. The fact that mutations of FOXP2 in humans result in speech impairments shows that it plays a role in speech development, but the nature of its role remains unclear. It might play a very specific role, for example, by orchestrating a whole set of genes that switch brain development from an ancestral program to a human program that causes cells and connections to differentiate into systems that sustain speech or language. It might even regulate the development of other parts of the anatomy, such as the lungs and larynx, involved in speech production. Alternatively, FOXP2 might have a permissive role, for example, by regulating some aspects of cell behavior required for the normal development of language systems, but also for the normal development of other structures and systems. Both options would be consistent with the action of a loss-of-function mutation in FOXP2, such as the R553H mutation in the KE family. In neither case, however, do we have a direct connection between language and the specific FOXP2 substitutions that took place in human evolution (T303N and N325S). There is not much question that these changes were the result of selection, and that they affect gene expression in the brain. However, given the widespread pattern of FOXP2 gene expression in the body, those substitutions are likely to affect gene expression in other organs, so it remains possible that the substitutions were driven by selection acting on non–speech-related parts of the brain or nonbrain tissues and organs. Humans are, after all, not just apes with unusually large, complex brains: other aspects of anatomy and physiology were extensively modified in human evolution as well. It could also be the case that FOXP2 has a speech- or language-specific function in the human brain, by virtue of the action of other transcription factors that bind to the same promoters in brain cells targeted by human FOXP2. However, then we would be talking about the interactions of genes involved in building a human organism, rather than a single gene, and it still would not be clear, without additional evidence, that the amino acid substitutions in FOXP2 were selected for their effects on developmental pathways specific to language.

It would seem that the crux of the problem with tying FOXP2 to language is that we are trying to relate a multifunctional gene to a complex, high-level phenotype, by which I mean a phenotype that encompasses a diverse collection of tissues and cell types. It is probably not realistic to think that the development of such systems have simple genetic triggers and are the products of epigenetic programs acting in isolation from other epigenetic programs. This conclusion merely restates two of the important lessons of experimental population genetics: first, that most phenotypes arise through the interactions of multiple genes (the principle of epistasis), and, second, that most genes influence multiple phenotypes (the principle of pleiotropy) (88, 89).