Accelerated evolution of oligodendrocytes in human brain

Abstract

Recent discussions of human brain evolution have largely focused on increased neuron numbers and changes in their connectivity and expression. However, it is increasingly appreciated that oligodendrocytes play important roles in cognitive function and disease. Whether both cell-types follow similar or distinctive evolutionary trajectories is not known. We examined the transcriptomes of neurons and oligodendrocytes in the frontal cortex of humans, chimpanzees, and rhesus macaques. We identified human-specific trajectories of gene expression in neurons and oligodendrocytes and show that both cell-types exhibit human-specific upregulation. Moreover, oligodendrocytes have undergone accelerated gene expression evolution in the human lineage compared to neurons. The signature of acceleration is enriched for cell type-specific expression alterations in schizophrenia. These results underscore the importance of oligodendrocytes in human brain evolution.

Cell-type and cytosine context-specific evolution of DNA methylation in the human brain

“…Here, we present novel comparative analyses of neuron-and oligodendrocyte-specific whole-genome DNA methylomes of humans, chimpanzees, and rhesus macaques. By integrating these data with transcriptome data from the same individuals 9 and recent data from studies of bulk and cell-type specific epigenetic and transcriptomic modifications of human brains 2,10-12 , we demonstrate dramatic changes of DNA methylation in a cell-type and cytosine context-specific manner during human brain evolution, impacting the human brain regulatory landscape and disease susceptibility.…”

“…This gene, which is an RNA binding protein involved in myelination and oligodendrocyte differentiation 17 , is encompassed in its entirety by a DMR in all three species so that it is hypomethylated in oligodendrocytes while hypermethylated in neurons. Gene expression data from matched samples 9 shows that QKI is up-regulated in oligodendrocytes compared to neurons in all three species (P < 10 -7 in all three species, Methods), indicating that cell-type specific regulation may be facilitated by DNA methylation. Interestingly, the absolute methylation difference between neurons and oligodendrocytes was significantly more pronounced in the evolutionarily 'old' DMRs conserved in all three species compared to those recently evolved in human ( Figure 1F; results of the same comparison using chimpanzee DMRs are also consistent, Supplementary Figure S5).…”

“…We selected Brodmann area 46 (BA46) from dorsolateral prefrontal cortex (also referred to as 'prefrontal cortex' or 'cortex' henceforth), which is involved in higher-order cognitive functions that have likely undergone marked changes in human evolution 13,14 . Neuronal (NeuN+) and oligodendrocyte (OLIG2+) cell populations were isolated using fluorescence-activated nuclei sorting (FANS) as previously described 8,9 . We used wholegenome bisulfite sequencing (WGBS) to generate DNA methylomes at nucleotide resolution for NeuN+ and OLIG2+ populations (Supplementary Figure S1).…”

“…CG DMRs tend to show reduction of DNA methylation (hypomethylation) in human prefrontal cortex compared to chimpanzee in both cell-types ( Figure 2B). While most previous studies focused on neurons, recent studies have begun to unveil the functional and evolutionary importance of oligodendrocytes-specific changes 9,18 . Indeed, we identified a substantial number of human-derived hypomethylated DMRs specific to oligodendrocytes (Figure 2A and 2B).…”

“…Indeed, we identified a substantial number of human-derived hypomethylated DMRs specific to oligodendrocytes (Figure 2A and 2B). To examine the transcriptional impact of cell-type epigenetic specializations of the human brain, we analyzed gene expression data from the same individuals and nuclei populations 9 . Hypomethylation near transcription start sites is associated with up-regulation of genes 19 .…”