The development of human brain is an immensely complex process, which is likely reflected in the complexity of the underlying transcriptional processes. Gene expression and its precise spatio-temporal regulation, particularly by histone modifications and non-coding RNAs, are crucial for normal human brain development and are thought to be altered in major developmental psychiatric disorders, such as autism spectrum disorders (ASD). Moreover, changes in the developmental brain transcriptome are likely the major contributors to the evolution of the most distinctly human aspects of cognition, some of which are also affected in ASD and other psychiatric disorders However, our understanding of transcriptional and epigenetic processes involved in the development, evolution and dysfunction of the human brain is still elusive. Furthermore, most of our knowledge of transcriptional processes in the human brain is limited to the expression of protein coding genes. Given that the genomes of humans and other mammals have approximately the same protein-coding complexity, there is likely an additional reservoir of transcriptional complexity, especially in organs such as the brain, which has many structurally and functionally distinct regions in humans. This view is corroborated by recent findings of the ENCODE consortium, which found many cis-acting regulatory regions and that 60% of the human genome is transcribed, with a majority of the transcripts belonging to non-coding RNAs. Moreover, these and other studies have also uncovered pervasive involvement of regulatory DNA variations in common human diseases and evolution. However, how these findings on non-coding elements in cell lines relate to the complexity of human brain development and dysfunction is still largely unknown. The objective of this proposal is to employ unbiased and genome-wide approaches to (1) discover and characterize developmentally regulated and human-specific non-coding functional genomic elements in multiple regions of the developing human and non-human primate brains, (2) and elucidate their role(s) in the molecular pathophysiology of ASD, by using genomic analyses of post-mortem ASD brains, by screening for de novo mutations in ASD quartets, and by modeling functional consequences of ASD-associated elements in the developing mouse brain.

Public Health Relevance

Non-coding functional genomic elements play a crucial role in normal human brain development by regulating gene transcription. These elements are thought to be altered in major developmental psychiatric and neurological disorders. Thus, the identification and functional characterization of non-coding elements in human neurodevelopment may lead to development of new and more effective treatments of major brain disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01MH103339-01
Application #
8677515
Study Section
Special Emphasis Panel (ZMH1-ERB-C (03))
Program Officer
Senthil, Geetha
Project Start
2014-06-15
Project End
2017-05-31
Budget Start
2014-06-15
Budget End
2015-05-31
Support Year
1
Fiscal Year
2014
Total Cost
$1,542,279
Indirect Cost
$585,172
Name
Yale University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Willsey, A Jeremy; State, Matthew W (2015) Autism spectrum disorders: from genes to neurobiology. Curr Opin Neurobiol 30:92-9