A new paper in Nature (Konopka et al. 2009) reports on microarray expression comparisons of human and chimpanzee-specific versions of FOXP2. The change of two amino acids in the human version has some pretty large consequences for the expression of other genes.
An accompanying essay by Martin Dominguez and Pasko Radic (2009) sums up the study in a paragraph:
To further understand what FOXP2 does on a molecular level, two articles have revealed some of its probable targets, but neither study compared the regulatory effects of human and ancestral FOXP2. This is precisely what Konopka and colleagues have done, using whole-genome arrays to detect differences in gene expression in human neuronal cell lines expressing either human FOXP2 (FOXP2human) or the ancestral protein, FOXP2chimp. The authors find that a substantial number of FOXP2 target genes are differentially regulated by FOXP2human and FOXP2chimp. Many of these genes met the criteria for positive selection during human evolution (although the authors had no way of assessing their statistical significance). This places their findings in harmony with previous results that show FOXP2-related genes as evolutionary arbiters. Because the authors examine human-specific gene regulation by FOXP2, their work may provide our first window on the co-evolution of regulatory networks that are important for human-specific features such as language, which probably require a number of genetic changes working in concert.
The "FOXP2" is not italicized here, because the passage refers to the protein product. I point that out to remind everybody that many important insights about gene function can only come from biochemical analysis of the resulting gene products. Most of us in paleoanthropology, even in the broadest sense encompassing genetics, don't
What I really like about the result is that it shows FOXP2 is not some "magic gene" that suddenly triggered a cognitive revolution. It's a transcription factor that affects cell proliferation, with effects that cascade in many tissues. And it's highly conserved -- which means it's not like you could just switch it to a different form and expect everything to go right. The kind of genetic comparison that I can do shows the possibility of coevolution:
Previously, we identified ChIP-chip targets of FOXP2 that themselves were also under positive selection6. We hypothesized that networks of genes important for language circuitry had been positively selected through selective pressure on human brain evolution. Thus, we also examined whether any differential FOXP2 targets were themselves under positive selection. Five genes (AMT, C6orf48, MAGEA10, PHACTR2 and SH3PXD2B) met the standard criteria of Ka/Ks > 1.0 for positive selection on the human lineage (where Ka indicates the rate of non-synonymous substitutions and Ks indicates the rate of synonymous substitutions; Supplementary Table 9). These data, along with the haCNS and expression data mentioned above, suggest that a subset of differential FOXP2 targets may have co-evolved to regulate pathways involved in higher cognitive functions.
It seems to me that a cascade of genetic changes may have laid the groundwork for this regulatory shift, and that human populations may still be catching up to that shift today. Changes in these widely-interacting "hub" proteins have to be net good (or at least neutral) or they wouldn't have happened. But that doesn't mean that all their consequences are good -- they drag along a lot of bad effects with the good ones. So such changes may be followed by a series of genetic aftershocks -- changes in the "spoke" genes with functions compromised by the developmental/regulatory shift. Those changes might still be ongoing.
Nor is FOXP2 the only candidate for such a system of genetic changes. The "haCNS" observation was this:
A significant number of the differentially expressed genes [considering human- and chimp-FOXP2] are also associated with human-specific accelerated highly conserved non-coding sequences (haCNS), but not with chimpanzee highly conserved non-coding sequences....
More on FOXP2:
Dominguez MH, Rakic P. 2009. Language evolution: The importance of being human. Nature 462:169-170. doi:10.1038/462169a
Konopka G, Bomar JM, Winden K, Coppola G, Jonsson ZO, Gao F, Peng S, Preuss TM, Wohlschlegel JA, Geschwind DH. 2009. Human-specific transcriptional regulation of CNS development genes by FOXP2. Nature 462:213-217.