Recent methodological advances in genomics and neuroscience have made it possible, for the first time, to determine how the human brain differs from that of other species. This research has revealed differences ranging from long-range neuronal connectivity to molecular changes, such as gene expression. Identifying these human-specific characteristics is vitally important for understanding common neurological and psychiatric diseases such as schizophrenia, autism, and Alzheimer's, diseases that have no definite counterparts in other primates and involve regions of the brain that underwent dramatic changes in size and internal organization in human evolution. However, the molecular mechanisms that underlie these diseases remain elusive. Our preliminary study of DNA methylation provides clues to these mechanisms, demonstrating that genes associated with neuropsychiatric disorders exhibit highly divergent DNA methylation patterns in human brains compared to non-human primate brains. Moreover, several human-specific gene co-expression networks that are strongly associated with neuropsychiatric disorders are enriched in genes that harbor human-specific DNA methylation signatures. In light of these observations, and of the emerging link between epigenomic markers and neuropsychiatric disorders, the systematic study of human epigenomic specializations promises to deepen our understanding of the molecular mechanisms that contribute to neuropsychiatric diseases and foster development of novel therapeutic interventions. The objectives of this project are to: (1) identify human-brain specific DNA methylation patterns; (2) elucidate the role of DNA methylation changes in the regulation of human-specific gene expression and co- expression networks; and (3) test the relevance of these epigenomic and transcriptomic changes in the context of neuropsychiatric diseases. We will examine two higher-order cortical regions from multiple human, chimpanzee, and macaque brains, drawing on the extensive collections of archival brain tissue available at the Yerkes National Primate Research Center. This comparative framework will enable us to pinpoint DNA methylation changes that accompanied changes in human brain structure and function. The link between human brain molecular specialization and human neuropsychiatric disorders will be verified by comparing control human brains to brains of schizophrenia patients, obtained from the Dallas Brain Collection (DBC) at UT Southwestern. The proposed studies of this multiple-PI and collaborator effort will leverage complementary and intersecting interests in epigenetics and evolution (Yi), comparative primate neurobiology (Preuss), and molecular neuroscience (Konopka). The application of our combined expertise to the analysis of the rich collection of DBC brain-disorder samples will promote discoveries of novel epigenetic mechanisms of neuropsychiatric disorders and provide the foundation for new insights and novel clinical approaches.

Public Health Relevance

This project will identify human brain specific patterns of DNA methylation, gene expression, and gene co- expression networks, and how these patterns are modified in the brains of schizophrenia patients. Such knowledge is central to a comprehensive understanding of molecular mechanisms of neuropsychiatric disorders. 1

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH103517-04
Application #
9412884
Study Section
Molecular Neurogenetics Study Section (MNG)
Program Officer
Meinecke, Douglas L
Project Start
2015-04-01
Project End
2020-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Georgia Institute of Technology
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
097394084
City
Atlanta
State
GA
Country
United States
Zip Code
30318
Mendizabal, Isabel; Zeng, Jia; Keller, Thomas E et al. (2017) Body-hypomethylated human genes harbor extensive intragenic transcriptional activity and are prone to cancer-associated dysregulation. Nucleic Acids Res 45:4390-4400
Huh, Iksoo; Wu, Xin; Park, Taesung et al. (2017) Detecting differential DNA methylation from sequencing of bisulfite converted DNA of diverse species. Brief Bioinform :
Yi, Soojin V (2017) Insights into Epigenome Evolution from Animal and Plant Methylomes. Genome Biol Evol 9:3189-3201
Yin, Hongyan; Wang, Guangyu; Ma, Lina et al. (2016) What Signatures Dominantly Associate with Gene Age? Genome Biol Evol 8:3083-3089
Mendizabal, Isabel; Yi, Soojin V (2016) Whole-genome bisulfite sequencing maps from multiple human tissues reveal novel CpG islands associated with tissue-specific regulation. Hum Mol Genet 25:69-82
Konopka, Genevieve; Roberts, Todd F (2016) Insights into the Neural and Genetic Basis of Vocal Communication. Cell 164:1269-1276
Mendizabal, Isabel; Shi, Lei; Keller, Thomas E et al. (2016) Comparative Methylome Analyses Identify Epigenetic Regulatory Loci of Human Brain Evolution. Mol Biol Evol 33:2947-2959
Keller, Thomas E; Han, Priscilla; Yi, Soojin V (2016) Evolutionary Transition of Promoter and Gene Body DNA Methylation across Invertebrate-Vertebrate Boundary. Mol Biol Evol 33:1019-28
Wang, Guang-Zhong; Belgard, T Grant; Mao, Deng et al. (2015) Correspondence between Resting-State Activity and Brain Gene Expression. Neuron 88:659-66
Glastad, Karl M; Goodisman, Michael A D; Yi, Soojin V et al. (2015) Effects of DNA Methylation and Chromatin State on Rates of Molecular Evolution in Insects. G3 (Bethesda) 6:357-63

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