Elevated gene expression levels distinguish human from non-human primate brains

Abstract

Little is known about how the human brain differs from that of our closest relatives. To investigate the genetic basis of human specializations in brain organization and cognition, we compared gene expression profiles for the cerebral cortex of humans, chimpanzees, and rhesus macaques by using several independent techniques. We identified 169 genes that exhibited expression differences between human and chimpanzee cortex, and 91 were ascribed to the human lineage by using macaques as an outgroup. Surprisingly, most differences between the brains of humans and non-human primates involved up-regulation, with approximately 90% of the genes being more highly expressed in humans. By contrast, in the comparison of human and chimpanzee heart and liver, the numbers of up- and down-regulated genes were nearly identical. Our results indicate that the human brain displays a distinctive pattern of gene expression relative to non-human primates, with higher expression levels for many genes belonging to a wide variety of functional classes. The increased expression of these genes could provide the basis for extensive modifications of cerebral physiology and function in humans and suggests that the human brain is characterized by elevated levels of neuronal activity.

Fig. 1.

Gene expression analysis of human, chimpanzee, and rhesus macaque cerebral cortex. (A) Dendrogram showing the hierarchical clustering of the different cortex samples according to the hybridization signals of 9,733 probe sets detected in at least one of the samples from any species (Hs1–5, humans; Pt1–4, chimpanzees; Mm1–4, rhesus macaques). FP, frontal pole; MFG, medial frontal gyrus; IPL, inferior parietal lobule; aIT, anterior inferotemporal cortex; STG, superior temporal gyrus; TP, temporal pole. (B) Hybridization levels for 246 probe sets that show differences in signal intensity between human and chimpanzee cortex. Columns correspond to the different cortex samples in the same order as in the dendrogram. Rows represent the individual probe sets with their identifying number indicated (Right) (see Table 2). For each probe set, red, green, and black indicate increased, decreased, and equal hybridization levels relative to the median, respectively. Hierarchical cluster analysis classified the probe sets into four different groups related to their species-specific hybridization pattern. (C) Expression levels of 21 genes showing differences between humans and chimpanzees by real-time RT-PCR. The y axis corresponds to the average expression level in three chimpanzees (Pt, orange) and three rhesus macaques (Mm, yellow) relative to three humans (Hs, red). Standard deviation within each species is indicated by error bars. (D) Relative hybridization levels in human and non-human primate cortex samples of 37 genes interrogated by using cDNA arrays. The y axis represents the base-2 logarithm of the average hybridization signal ratio of four human–chimpanzee comparisons (Hs/Pt, dark green) and four human–rhesus comparisons (Hs/Mm, light green). Positive and negative values denote higher and lower hybridization levels, respectively, in humans than in non-human primates. In C and D, horizontal lines separate the genes that show increased expression in humans and in chimpanzees. The gene symbol or UniGene accession number is indicated inside each graph.

Fig. 2.

Histological study of gene-expression differences in the cortex between humans and non-human primates. In situ hybridization confirms that CA2 is expressed at higher levels in the cortex of humans than in chimpanzees or rhesus macaques (Upper). Note the particularly strong labeling for CA2 in the white matter (w) immediately below the cortical gray matter (g). TWIST is weakly expressed in human cortex compared with chimpanzees and macaques (Lower), where expression is strongest in cortical layers II–VI. Arrows point to the regions of expression of both genes. (Bar = 1 mm.)