These genes are significantly enriched for the GO categories’ cytokine receptor activity (p = 6.0 × 10−3) and the JAK/STAT signaling pathways (p = 1.0 × 10−3) in the FP (IL11RA, IL13RA2, and GHR), for carboxylic acid catabolic process (p = 3.3 × 10−3) in the HP (ASRGL1, CYP39A1, and SULT2A1), and for synaptic transmission (p = 3.5 × 10−2) in the CN (LIN7A, MYCBPAP, and EDN1). Together, NVP-BGJ398 these data suggest that human-specific gene evolution is important for signaling pathways in the brain. We next applied weighted gene coexpression network analysis (WGCNA) (Oldham et al., 2008) to build both combined

and species-specific coexpression networks, so as to examine the systems-level organization of lineage-specific gene expression differences. We constructed networks in each

species separately and performed comparisons GSI-IX in vitro of these networks to insure a robust and systematic basis for comparison (Oldham et al., 2008). The human transcriptional network was comprised of 42 modules containing 15 FP modules, 6 CN modules, 2 HP modules, and 19 modules not representing a specific brain region (Figure 3 and Tables S2 and S3; Supplemental Experimental Procedures). The FP samples correlated less with the CN and HP samples, using a composite measure of module gene expression, the module eigengene, or first principal component (Oldham et al., 2008) (data not shown). The chimp network analysis yielded 34 modules, including 7 FP modules, 9 CN modules, 7 HP modules, and 11 modules that were unrelated to a specific brain region (Figure 3 and Tables S2 and S3). The macaque analysis yielded 39 modules with 6 FP unless modules, 8 CN modules, 5 HP modules, and 20 modules not related to a specific brain region (Figure 3 and Tables S2 and S3). Thus, only in human brain were more modules related to FP than either of the other regions, consistent with increased cellular and hence transcriptional complexity in

FP relative to the other regions. While the smaller number of chimpanzee (n = 15) and macaque (n = 12) samples compared to human (n = 17) samples could potentially affect the outcome of the network analysis, we used the same thresholding parameters, and there were equivalent numbers of human and chimpanzee FP samples (n = 6), similar numbers of total modules in human and macaque samples (42 and 39, respectively), and proportionally more FP modules compared to total modules in human samples (18/42 = 43%) compared to chimpanzee (8/34 = 23%) or macaque (5/39 = 13%), mitigating this concern. This indicates that even within a single region of human frontal lobe, transcriptome complexity is increased with regards to other primates. We next determined the conservation of the modules defined in humans in the other species (see Supplemental Experimental Procedures; Table S3).