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Developmental Biology - Brain Disorders

Roots of Neuropsychiatric Disease

Genes have increased chance for creating disorder in a developing brain...

According to research from Yale University, our developing brain is at the root of neuropsychiatric diseases. The most comprehensive gene analysis of the human brain ever undertaken is revealing how changes our brain undergoes during development - are the root causes of neuropsychiatric illnesses such as those on the autism spectrum, as well as schizophrenia.

This multi-institutional analysis of almost 2,000 brains integrates the complex choreography of brain development with function. It was published Dec. 14 as 11 studies appearing in a special edition of the journal Science along with two sister publications.

Four of the studies were spearheaded by a variety of disciplines at Yale University, in an ambitious effort to join neuroscience with data science. The Yale-led research illustrates a host of new tools scientists at 15 institutions used to find the molecular basis of neuropsychiatric diseases — the ultimate goal of the PsychENCODE Consortium founded in 2015 by the National Institutes of Health (NIH).

According to research headed by Mark Gerstein, Yale's Albert L Williams Professor of Biomedical Informatics, risk variations influence the function of genes very early in development (and throughout a lifetime) - but have a greater chance of manifesting as symptoms when first forming into distinct brain modules during early development.

Healthy brain development and neurological function rely on precise regulation of gene function (expression) which varies substantially by region and cell type in the human brain. Nenad Sestan PhD, professor of neuroscience, comparative medicine, genetics, and psychiatry, and corresponding or co-corresponding author of two of the major Science papers, found differences in cell types varies between 16 regions of the human brain during development. These cell types may be key in determining whether genetic risk translates into a neuropsychiatric disorder.

It was also found that the greatest variation in brain cell type and gene expression activity happens (1) early in prenatal development, (2) drops in late in pregnancy and early childhood, and (3) increases again in early adolescence. This "cup-shaped" pattern of development is also seen in rhesus macaque monkeys, a primate species closely related to humans. Moreover, in the same study led by Sestan's lab, researchers identified which features of brain development differ between humans and macaque, including the unique human gene expression signatures of late childhood.
During these 3 periods of greatest developmental change, risk susceptibility genes tend to form distinct networks (modules) in specific brain areas and at specific times.

• Autism tend to form early in development.
• Schizophrenia, IQ and neurosis form later.

This may explain why autism appears in early childhood, while schizophrenia appears in early adulthood. Genes linked to mental illnesses are also expressed in specific cell types, which helps determine the scope and effect of specific disease-associated genetic variations. Molecular events that lead to neuropsychiatric disorders can precede symptoms by months or even years, researchers observed. "Risk factors for disease are always present, but they are not equally manifested across time and space," Sestan explains.

Researchers coaxed human stem cells derived from the tissue of individuals to develop into brain organoids — mimicking early development of the human brain. Organoids recapitulate the first trimester human brain, when neural stem cells start differentiating into a multitude of neuron types making up the brain. They allow researchers to identify and follow gene regulatory networks active in early brain development. The early brain carries considerable genetic and environmental risk for developmental disorders. Known autism risk genes - and the regulatory elements that control their activity - are highly expressed in organoids. "This model can potentially reveal how those genetic risk variants lead to disease," explains Flora Vaccarino PhD, Yale's Harris Professor in the Child Study Center and professor in the Department of Neuroscience, and co-corresponding author of one of the major Science papers.

The massive amounts of information collected by PsychENCODE researchers is organized in an accessible data "atlas." Data scientists can employ deep-learning analysis or a machine-learning approach loosely inspired by human cognition to find clues to combat the progression of neuropsychiatric disorders in individuals. For example, scientists can now integrate information from single-cell sequencing to a more traditional genomic measurement of 'bulk' tissue samples, to capture differences amongst a large population of people in different stages of development.

This approach allowed Gerstein's lab to reveal that much of the differences in gene expression between individuals is due to changing proportions of basic cell types, such as excitatory neurons. An important example being the Glutamatergic synapse. Glutamate is a small amino acid neurotransmitter and is the main excitatory neurotransmitter in our central nervous system.

To broaden our understanding of human neurodevelopment, we profiled transcriptomic and epigenomic landscapes across brain regions and/or cell types for the entire span of prenatal and postnatal development. Integrative analysis revealed temporal, regional, sex, and cell type–specific dynamics. We observed a global transcriptomic cup-shaped pattern, characterized by a late fetal transition associated with sharply decreased regional differences and changes in cellular composition and maturation, followed by a reversal in childhood-adolescence, and accompanied by epigenomic reorganizations. Analysis of gene coexpression modules revealed relationships with epigenomic regulation and neurodevelopmental processes. Genes with genetic associations to brain-based traits and neuropsychiatric disorders (including MEF2C, SATB2, SOX5, TCF4, and TSHZ3) converged in a small number of modules and distinct cell types, revealing insights into neurodevelopment and the genomic basis of neuropsychiatric risks.

Mingfeng Li, Gabriel Santpere, Yuka Imamura Kawasawa, Oleg V. Evgrafov, Forrest O. Gulden, Sirisha Pochareddy, Susan M. Sunkin, Zhen Li, Yurae Shin, Ying Zhu, André M. M. Sousa, Donna M. Werling, Robert R. Kitchen, Hyo Jung Kang, Mihovil Pletikos, Jinmyung Choi, Sydney Muchnik, Xuming Xu, Daifeng Wang, Belen Lorente-Galdos, Shuang Liu1, Paola Giusti-Rodríguez, Hyejung Won, Christiaan A. de Leeuw, Antonio F. Pardiñas, BrainSpan Consortium, PsychENCODE Consortium, PsychENCODE Developmental Subgroup, Ming Hu, Fulai Jin, Yun Li, Michael J. Owen, Michael C. O’Donovan, James T. R. Walters, Danielle Posthuma, Pat Levitt, Daniel R. Weinberger, Thomas M. Hyde, Joel E. Kleinman, Daniel H. Geschwind, Michael J. Hawrylycz, Matthew W. State, Stephan J. Sanders, Patrick F. Sullivan, Mark B. Gerstein, Ed S. Lein, James A. Knowles, Nenad Sestan.

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Dec 14, 2018   Fetal Timeline   Maternal Timeline   News   News Archive

Molecular events that lead to neuropsychiatric disorders can precede
symptoms by months or even years. Image Credit: SCIENCE.

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