, 2007). Rather, protein-coding genes in the nervous system have on average fewer nonneutral changes and thus are under increased purifying selection. This is consistent with the notion that

human CNS complexity yields evolutionary constraint. However, the increased evolutionary constraint on brain-expressed genes overall does not preclude adaptive evolution of individual genes; rather, it puts them into stronger relief. Genome-wide comparisons reveal that approximately 500–1,000 genes are likely under strong positive selection in humans based on changes in their coding sequence (Clark et al., 2003, Chimpanzee Sequencing and Analysis Consortium, 2005 and Scally et al., 2012). Although brain genes are not overall under positive selection, buy Vemurafenib there is an enrichment for brain-related functions among those that are (Kamada et al., 2011 and Liu et al., 2012a). One particularly salient example is the transcription factor FoxP2, which was originally identified for its role in a rare

speech and language disorder, and more recently with developmental dyspraxia in humans (Noonan et al., 2006). Remarkably, sequencing of the Neanderthal Dorsomorphin order and Denisovan genomes revealed that they share the human-derived form of FoxP2 (Meyer et al., 2012 and Noonan et al., 2006). One of the human-derived changes was present in carnivores, reducing the statistical evidence for the adaptive evolution of FoxP2. Here, the power of modern molecular genetics and neuroscience was brought to bear in two studies, one in vitro

and one in vivo, which tested the functional impact of the two amino acid changes. In the first, mouse FoxP2 was humanized (hFoxP2) and compared with the endogenous mouse form, revealing functional changes in striatal circuitry coupled with cellular alterations, including increased dendritic length in the mouse with hFoxP2, consistent with previous analyses of FoxP2 targets (Spiteri et al., 2007 and Vernes et al., 2011). In the second study (Konopka et al., 2009), overexpression of the human and chimpanzee FoxP2 in human cells was performed to compare its transcriptional targets, revealing striking differences between the two species’ FoxP2 forms, many of which reflected in vivo gene expression differences observed tuclazepam between human and chimpanzee brain. In addition to genes important for neurodevelopment and synaptic function, human differential FoxP2 targets also included genes involved in branchial arch formation and craniofacial development, which suggests potential coevolution of both the CNS and articulatory structures necessary for spoken language (Konopka et al., 2009). Additional layers of complexity exist; recent studies comparing the hFoxp2 to the mouse version suggest that FoxP2 function may extend beyond circuit formation and plasticity to directing neural progenitor proliferation (Tsui et al., 2013), thus providing another window for directing cortical evolution.