Patterns and functions of genes with human-specific expression in PFC. (A) Five major human-specific gene expression modules found in the PFC. Expression profile of PFC modules measured using RNA-seq data set 1 (B) and data set 2 (C). In A through C, each point represents an individual (red, human; blue, chimpanzee; green, macaque), the lines in A and C show cubic spline curves. (Error bars) SD across genes in a module. (x-axis) Age in log2 scale. Expression levels of all genes were standardized to mean = 0 and SD = 1 before averaging. The titles on top of each panel show module information; numbers in A show number of genes in each module and in B and C show the number of module member genes expressed in RNA-seq. (D) Three KEGG pathways (Kanehisa et al. 2008) significantly enriched in module 1 genes: neuroactive ligand-receptor interaction, calcium signaling, and long-term potentiation. Proteins or protein complexes containing module 1 genes are shown in red, containing module 1–like genes in light red, showing expressed genes in gray, and without expressed genes as empty circles. Genes with Pearson correlation r > 0.5 between their expression change with age, and the module 1 mean expression change with age in all three species was classified as module 1–like genes. (Blue) Three neurotransmitters (glutamate [Glu], aspartate [Asp], and GABA) associated with the pathways and showing human-specific profiles. (Arrows) Interactions based on the KEGG pathway annotation. (E) Concentration profiles of the three human-specific neurotransmitters: glutamate, aspartate, and GABA, in the PFC of the three species (red, human; blue, chimpanzee; green, macaque). To reduce individual variation, individuals with similar ages were combined in four age groups, separated by a gray dashed line. The distribution of neurotransmitters' concentrations from samples within each age group is shown in a boxplot. In the youngest age group (0–1 mo), the neurotransmitters' concentrations in humans were lower than in chimpanzees and macaques. Significance of the difference between human–macaque or human–chimpanzee comparisons is shown by the long or short lines above the youngest age group (one-sided z-test: ***P < 0.001; oP < 0.1; Supplemental Methods).
