14 October 2003. If humans genetically are almost identical to their primate relatives, what is it that makes us smarter? This question has befuddled scientists for some time. In this week’s PNAS early online edition, researchers at the Salk Institute for Biological Studies, La Jolla, with colleagues elsewhere in California and in Georgia, suggest that the greater brain power is due to elevated gene expression. This supports work reported in 2002 by Svante Paabo and colleagues at the Max-Plank-Institute for Evolutionary Anthropology in Leipzig, Germany (see ARF related news story).
First author Mario Caceres and colleagues, working with Carolee Barlow at Salk, compared gene expression profiles among the cerebral cortexes of humans, chimpanzees, and macaques. Using oligonucleotide probes that hybridize to about 10,000 different genes, the authors found 169 differentially expressed genes of which 91 were identified as being human. Significantly, 90 percent of these were upregulated. By contrast, examination of gene expression patterns in liver and heart revealed that humans had almost equal numbers of up- and downregulated genes compared to the other primates. The authors suggest that the increased gene expression in the cortex “could provide the basis for the extensive modifications of cerebral physiology and function in humans.” To eliminate systematic bias that may be introduced by the techniques used, Caceres used RT-PCR to confirm the results for about one-third of the upregulated genes.
The authors go so far as to suggest that it is the elevated expression that leads to increased levels of neuronal activity, which in turn explain our more refined cognitive and behavioral functions. (With the exception of larger overall size, particularly of the neocortex, human and other primate brains are structurally quite similar.) In support of this, they found that many of the upregulated genes, which fell into several categories, are involved in synaptic transmission and energy metabolism (e.g., SYN47, involved in synaptic plasticity, KIF3a in axonal transport, and CA2, related to generation and transport of lactate).
One potential benefit of this type of research is the identification of factors that predispose humans to various neurodegenerative diseases, such as Alzheimer’s, that are rare in primates. It is interesting, then, that Caceres found elevated expression of various genes involved in lipid and steroid metabolism, because cholesterol and ApoE4 are known risk factors for AD. The authors also suggest that the upregulation of several chaperones in humans could confer some protection against diseases of protein misfolding.-Tom Fagan.
Caceres M, Lachuer J, Zapala MA, Redmond JC, Kudo L, Geschwind DH, Lockhart DJ, Preuss TM, Barlow C. Elevated gene expression levels distinguish human from non-human primate brains. Proc Natl Acad Sci U S A. 2003 Oct 28;100(22):13030-5. Epub 2003 Oct 13. Abstract