severe reduction of brain size that characterizes microcephaly in humans (Bond et al., 2002; Jackson et al., 2002). During descent of the ape stem portion of the primate lineage to humans (approximately 25 to 6 Mya), positive selection acted on microcephalin’s protein-coding sequence, and during the past 6 million years in descent from the chimpanzee/human LCA to modern humans, positive selection acted on ASPM’s protein-coding sequence (Zhang, 2003b; Evans et al., 2004a,b; Kouprina et al., 2004; Wang and Su, 2004).
Language is also considered to be a distinctive human trait. There is evidence of accelerated evolution in the human terminal of the protein-coding sequence of Forkhead Box P2 (FOXP2) (Enard et al., 2002b; Zhang et al., 2002; Spiteri et al., 2007). This gene encodes a transcription factor that influences the expression levels of many brain-expressed genes. FOXP2 mutants have been found in humans with language dysfunction (Lai et al., 2001; MacDermot et al., 2005; Feuk et al., 2006), suggesting that adaptive evolution of FOXP2 may have contributed to the origin of modern human spoken language abilities (Enard et al., 2002b; Zhang et al., 2002). This adaptive evolution may have occurred in archaic humans ancestral to both Neanderthals and modern humans, an inference drawn from the finding that Neanderthal FOXP2 has the same two amino acid replacements that distinguish modern human FOXP2 from the orthologous chimpanzee protein (Krause et al., 2007). The chimpanzee FOXP2 patterns of brain transcriptional regulation differ somewhat from the modern human FOXP2 patterns (Konopka et al., 2009), although there is no direct evidence that the two-amino acid difference of chimpanzee FOXP2 from modern human FOXP2 causes language dysfunction. In addition to evidence suggesting FOXP2 has evolved adaptively in humans, five of the genes that FOXP2 regulates had themselves been under positive selection (Konopka et al., 2009). Several genes involved in the development of the auditory system also show evidence of adaptive evolution in modern humans (A.G. Clark et al., 2003).
A number of recent studies have examined gene expression in the brain transcriptomes of different primate species. More expression changes were observed in the human brain than in other primate brains (Enard et al., 2002a). In general, the majority of these changes involved increased expression (Cáceres et al., 2003). Among the genes found to be up-regulated in modern humans are genes involved in neuronal activity and metabolic processes (Cáceres et al., 2003; Uddin et al., 2004). Genes involved in oxidative phosphorylation (electron transport) are especially up-regulated in humans (Uddin et al., 2004). Most recently, Nowick and colleagues (2009) suggested that major differences in expression of brain-expressed genes observed between human and chimpanzee may be coordinated by a small number of transcription factors that show differential expression