A large number of mutations contributing to psychiatric disorders have been identified. However, the mechanisms by which these mutations cause these diseases are still unknown. Computational approaches that integrate large and heterogeneous datasets will play crucial role in predicting molecular mechanisms behind psychiatric disease mutations. In our recent study (Lin et al, Neuron, 2015) we demonstrated how spatio-temporal protein interaction networks could help to identify a pathway that is likely involved in regulating brain size in the 16p11.2 copy number variant deletion and duplication carriers. Here, we propose to use similar approaches to construct the isoform-level co-expression and protein interaction networks for predicting functional impact of the de novo splice site mutations from the patients with autism spectrum disorder (ASD). More than 80 splice site de novo mutations are currently identified in the ASD patients, but not a single disease mechanism is established for any of these mutations. We hypothesize that isoform-level networks will provide us with a more detailed and realistic picture of the processes that are disrupted by the ASD mutations in the brain. To test this hypothesis, we propose an integrative approach that combines network biology, CRISPR/Cas technology, transcriptomic and proteomic methods to predict and validate the impact of splice site mutations on cellular and molecular pathways in the human (iPSCs) and animal models of ASD. The ultimate goal of this project is to predict and validate specific pathways that are impacted by the de novo ASD splice site mutations. We will achieve this goal through the following specific aims: (1) Build and analyze isoform-level networks of brain co-expressed and physically interacting proteins; (2) Map de novo ASD mutations onto isoform-level networks to predict their functional impact; (3) Validate the disrupted networks and pathways using CRISPR/Cas technology in neuronal and animal models. The proposed study will discover and characterize cellular and molecular processes that are disrupted by the de novo splice site ASD mutations. The pathways identified in this study could represent important new targets for future therapeutic intervention.

Public Health Relevance

Our study will help to gain insights into a molecular mechanism of ASD that is impacted by the de novo splice site mutations. By predicting and investigating cellular and molecular changes as a result of these mutations, we will uncover the pathways that may represent high priority targets for future therapeutic interventions.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Special Emphasis Panel (ZMH1)
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Arguello, Alexander
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University of California, San Diego
Schools of Medicine
La Jolla
United States
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Herai, Roberto H; Negraes, Priscilla D; Muotri, Alysson R (2017) Evidence of nuclei-encoded spliceosome mediating splicing of mitochondrial RNA. Hum Mol Genet 26:2472-2479
Lin, Guan Ning; Corominas, Roser; Nam, Hyun-Jun et al. (2017) Comprehensive Analyses of Tissue-Specific Networks with Implications to Psychiatric Diseases. Methods Mol Biol 1613:371-402
Thomas, Charles A; Tejwani, Leon; Trujillo, Cleber A et al. (2017) Modeling of TREX1-Dependent Autoimmune Disease using Human Stem Cells Highlights L1 Accumulation as a Source of Neuroinflammation. Cell Stem Cell 21:319-331.e8
Pagel, Kymberleigh A; Pejaver, Vikas; Lin, Guan Ning et al. (2017) When loss-of-function is loss of function: assessing mutational signatures and impact of loss-of-function genetic variants. Bioinformatics 33:i389-i398