4.21.3.4 Genomic Data Provide Insights into Cortical Specializations. Recent studies of phylogenetic variation in gene p0240 sequences and expression provide additional insights into cortical specializations among hominoids. While most of these studies have been directed at determining the genetic basis for human neural uniqueness (b0215 Enard et al., 2002a; b02202002b; b0130 Caceres et al., 2003; b0210Dorus et al., 2004; b0795Uddinet al., 2004), some molecular data point to changes that occurred at earlier times in the hominoid radiation. For instance, all hominoids have evolved a novel biochemical mechanism to support high levels of glutamate flux in neurotransmission through theretroposition of the gene GLUD1 (b0105 Burki and Kaessmann, 2004). This duplicated gene, GLUD2,which is unique to hominoids, encodes an isotype of the enzyme glutamate dehydrogenase that is expressed in astrocytes. All hominoid GLUD2 sequences contain two key amino acid substitutions that allow the GLUD2 enzyme to be activated in astrocytes during conditions of high glutamatergic neurotransmitter flux. Concordant with this evidence for alterations in the molecular machinery necessary for enhanced neuronal activity in apes, ithas been shown that the gene encoding the cytochrome c oxidase subunit 4-1 underwent rapid non synonymous evolution in the hominoid stem,followed by purifying selection in descendent lineages (b0855 Wildman et al., 2002). Because these nucleotide substitutions have functional consequences for the manner and rate at which electrons are transferred from cytochrome c to oxygen, it is likely that these modifications were selected to serve the needs of cells with high aerobic energy demands,such as neurons.p0245 Also of significance, an alternative splice variant of neuropsin (type II) has originated in recent hominoid evolution (b0485Li et al., 2004). Neuropsin is expressed in hippocampal pyramidal neurons and is involved in neuronal plasticity. The high incidence of polymorphisms in the coding region of this protein in gibbons and orangutans, however, suggests that it may not be functional in these species. In contrast,the coding region of the type II splice form of neuropsin shows relatively little variation in gorillas,chimpanzees, and humans, signifying that it is maintained by functional constraint and that it might be involved in a molecular pathway important for learning and memory in these hominoids.