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between humans and chimpanzees. Interestingly, many of these transcription factors are associated with pathways involved in energy metabolism (Nowick et al., 2009).

In addition to changes in gene expression level, gene duplication events during human ancestry may have also contributed significantly to our brain evolution. All mammals possess a gene that encodes glutamate dehydrogenase 1 (GLUD1). Whereas GLUD1 is localized to both the mitochondria and cytoplasm where it functions in the metabolism of glutamate, a retrotransposon-mediated duplication event in the hominoid ancestor approximately 18 to 25 Mya (Burki and Kaessmann, 2004) resulted in a second GLUD-encoding gene (GLUD2) that is targeted specifically to the mitochondria (Rosso et al., 2008). Glutamate is the most common neurotransmitter in the brain. It is believed that positively selected amino acid substitutions in GLUD2 allow for more efficient energy metabolism of glutamate in the brain (Plaitakis et al., 2000, 2003; Rosso et al., 2008).


Neurons are the most energy-demanding cells of the modern human body (Attwell and Laughlin, 2001). The proliferation and pruning of neurons and their dendrites and the formation of the synaptic connections involved in learning are all energy-intensive processes. Thus it was not unexpected that aerobic energy metabolism (AEM) genes were found to be major targets of positive selection in the adaptive evolution of enlarged brains. This finding was made in a phylogenomic study that examined protein-coding sequence evolution during human ancestry (Uddin et al., 2008). In the time between the Old World monkey–ape LCA and the chimpanzee–human LCA, the most favored targets of positive selection were brain-expressed genes that code for mitochondrial functioning proteins, for example, proteins of the oxidative phosphorylation pathway (Uddin et al., 2008; Goodman et al., 2009). Although not brain-specific, many of these AEM genes are highly expressed in the adult human brain (Uddin et al., 2008). Moreover, these genes not only show evidence of adaptive evolution on the lineage to the LCA of humans and chimpanzees, but also on both the terminal human and terminal chimpanzee lineages. Considering that mitochondria play an essential central role in the aerobic production of energy, it may be inferred that the adaptive evolution of AEM genes improved the molecular machinery that facilitates the functioning of a high-energy-demanding encephalized brain.

Phylogenomic analysis of approximately 15,000 human coding sequences confirmed that AEM genes were favored targets of positive selection in the ape stem period of human ancestry (i.e., between 25 Mya

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