Species-Specific Changes in a Primate Transcription Factor Network Provide Insights into the Molecular Evolution of the Primate Prefrontal Cortex

Abstract

The human prefrontal cortex (PFC) differs from that of other primates with respect to size, histology, and functional abilities. Here, we analyzed genome-wide expression data of humans, chimpanzees, and rhesus macaques to discover evolutionary changes in transcription factor (TF) networks that may underlie these phenotypic differences. We determined the co-expression networks of all TFs with species-specific expression including their potential target genes and interaction partners in the PFC of all three species. Integrating these networks allowed us inferring an ancestral network for all three species. This ancestral network as well as the networks for each species is enriched for genes involved in forebrain development, axonogenesis, and synaptic transmission. Our analysis allows us to directly compare the networks of each species to determine which links have been gained or lost during evolution. Interestingly, we detected that most links were gained on the human lineage, indicating increase TF cooperativity in humans. By comparing network changes between different tissues, we discovered that in brain tissues, but not in the other tissues, the human networks always had the highest connectivity. To pinpoint molecular changes underlying species-specific phenotypes, we analyzed the sub-networks of TFs derived only from genes with species-specific expression changes in the PFC. These sub-networks differed significantly in structure and function between the human and chimpanzee. For example, the human-specific sub-network is enriched for TFs implicated in cognitive disorders and for genes involved in synaptic plasticity and cognitive functions. Our results suggest evolutionary changes in TF networks that might have shaped morphological and functional differences between primate brains, in particular in the human PFC.

Accelerated evolution of oligodendrocytes in human brain

“…Enrichment is based on a Fisher's exact test. X-axis shows the representative data included for this analysis (Berto and Nowick, 2018;Konopka et al, 2012;Somel et al, 2010;Sousa et al, 2017b). A) Bubble chart illustrates -log10(FDR) (X-axis) and Odds Ratio (Y-axis) of gene set enrichment for gene modules implicated in neuropsychiatric disorders (Gandal et al, 2018) and NeuN human-specific modules.…”

“…Doing so reduced the number of DEGs per million year due to smaller sample size and heterogeneity within and between species; however, downsampled DEGs show the same pattern of acceleration in OLIG2 compared with NeuN, further supporting the result that oligodendrocytes have undergone an evolutionary acceleration on the human lineage. We next examined previous gene expression studies of frontal cortex evolution (Berto and Nowick, 2018;Konopka et al, 2012;Somel et al, 2010;Sousa et al, 2017b) to assess how bulk tissue expression profiles may have been confounded by cell-type specific trajectories. We found that human-specific upregulated genes in the bulk tissue studies were enriched with human-specific NeuN upregulated DEGs.…”

“…Data were downloaded from respective NCBI GEO sources. Berto et al 2018 andKonopka et al 2012 provide species-specific differentially expressed genes within supplementary information (Berto and Nowick, 2018;Konopka et al, 2012). For the Somel et al microarray dataset (Somel et al, 2010), raw data were downloaded and analyzed with Affy in R (Gautier et al, 2004).…”

“…Deconvolution based on the Allen Brain Institute single nuclei data from human middle temporal gyrus (MTG)(Boldog et al, 2018). A) Primate transcriptomic meta-analysis data fromBerto et al (Berto and Nowick, 2018). B) Primate transcriptomic data from Konopka et al(Konopka et al, 2012).…”

Imitation: Neither instinct nor gadget, but a cultural starting point?

“…Genetic and morphological evidence show variations that lead to both the increase in general aspects of brain plasticity and in specific features of the human brain and presumably human cognition. Examples of the more general features are variations linked to the overall increase in the size of the human neocortex (Florio et al 2015;Gómez-Roblesa et al 2015) and to the disproportionately larger human frontal lobes (Berto & Nowick 2018). One notable variation that seems to enhance particular aspects of human brain plasticity is the increased depth of the superior temporal sulcus in the right hemisphere that is probably related to social communication (Leroy et al 2015).…”