Evolution of DNA methylation in the human brain

Hyeonsoo Jeong, Isabel Mendizabal, Stefano Berto, Paramita Chatterjee, Thomas Layman, Noriyoshi Usui, Kazuya Toriumi, Connor Douglas, Devika Singh, Iksoo Huh, Todd M. Preuss, Genevieve Konopka () and Soojin V. Yi ()
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Hyeonsoo Jeong: School of Biological Sciences, Georgia Institute of Technology
Isabel Mendizabal: School of Biological Sciences, Georgia Institute of Technology
Stefano Berto: UT Southwestern Medical Center
Paramita Chatterjee: School of Biological Sciences, Georgia Institute of Technology
Thomas Layman: School of Biological Sciences, Georgia Institute of Technology
Noriyoshi Usui: UT Southwestern Medical Center
Kazuya Toriumi: UT Southwestern Medical Center
Connor Douglas: UT Southwestern Medical Center
Devika Singh: School of Biological Sciences, Georgia Institute of Technology
Iksoo Huh: School of Biological Sciences, Georgia Institute of Technology
Todd M. Preuss: Yerkes National Primate Research Center, Emory University
Genevieve Konopka: UT Southwestern Medical Center
Soojin V. Yi: School of Biological Sciences, Georgia Institute of Technology

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: Abstract DNA methylation is a critical regulatory mechanism implicated in development, learning, memory, and disease in the human brain. Here we have elucidated DNA methylation changes during recent human brain evolution. We demonstrate dynamic evolutionary trajectories of DNA methylation in cell-type and cytosine-context specific manner. Specifically, DNA methylation in non-CG context, namely CH methylation, has increased (hypermethylation) in neuronal gene bodies during human brain evolution, contributing to human-specific down-regulation of genes and co-expression modules. The effects of CH hypermethylation is particularly pronounced in early development and neuronal subtypes. In contrast, DNA methylation in CG context shows pronounced reduction (hypomethylation) in human brains, notably in cis-regulatory regions, leading to upregulation of downstream genes. We show that the majority of differential CG methylation between neurons and oligodendrocytes originated before the divergence of hominoids and catarrhine monkeys, and harbors strong signal for genetic risk for schizophrenia. Remarkably, a substantial portion of differential CG methylation between neurons and oligodendrocytes emerged in the human lineage since the divergence from the chimpanzee lineage and carries significant genetic risk for schizophrenia. Therefore, recent epigenetic evolution of human cortex has shaped the cellular regulatory landscape and contributed to the increased vulnerability to neuropsychiatric diseases.

Date: 2021
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DOI: 10.1038/s41467-021-21917-7

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