Somatic mutations are de novo mutations that occur after fertilization. Once a cell has acquired a somatic mutation, all of its progenitors will also carry that mutation. Thus, if a cell acquires a mutation early in embryonic development, the mutation will be carried by many of the cells in the body. However, if the mutation occurs late in development, then only a few cells might carry it. Thus, it is possible to have mutations that only occur in the brain, or a small region of the brain. It has been known for a while that somatic mutations can cause cancer, and recent studies are showing that somatic mutations are associated with neurodevelopmental disorders resembling autism spectrum disorders (ASDs) both in terms of their high de novo mutation rate and in terms of their associated symptoms such as intellectual disability and epilepsy. We hypothesize that somatic mutations represent a significant cause of (ASDs) because of the high rate of de novo mutations associated with ASDs, the importance of somatic mutations in some genes known to cause ASDs, and the importance of somatic mutations in other developmental brain disorders with features that overlap ASDs. The technical and resource limitations that had prevented a systematic study of the role of somatic mutations in ASDs have now been overcome thanks to 1] Next-Generation Sequencing (NGS), which allows for the deep sequencing of genes and their transcripts with the ability to analyze each sequence, and 2] tissue banks that have collected brain specimens from individuals who had ASD. In this collaborative UO1 we will employ complementary approaches to systematically identify and functionally characterize somatic brain mutations associated with ASD. For causative somatic mutations identified in ASD brain, we will use techniques developed in our labs to examine individual brain cells for the presence of somatic mutation. This will provide us with a map of what regions of the brain, and what cells types in the brain carry these somatic mutations. We will also model and functionally characterize ASD- associated brain mutations in induced pluripotent cells and mice. This study could 1] improve the genetic diagnosis of ASD; by assessing the prevalence of somatic mutations as a cause of ASD, 2] provide a paradigm that may apply to other complex neuropsychiatric diseases (such as schizophrenia), and 3] improve our understanding of the mechanisms underlying ASD by creating a map of brain regions and cell types involved in ASD.

Public Health Relevance

For most patients the genetic causes of Autism Spectrum Disorders (ASDs) are not known. The work proposed in this application will help determine how often genetic changes limited to parts of the brain are an important cause of ASDs. Our research will further attempt to determine which parts of the brain are involved in ASD, thus improving our understanding of how the disease works and contribute to the development of diagnostic test to detect such changes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01MH106883-04
Application #
9418628
Study Section
Special Emphasis Panel (ZMH1)
Program Officer
Senthil, Geetha
Project Start
2015-05-01
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
Boston Children's Hospital
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
D'Gama, Alissa M; Woodworth, Mollie B; Hossain, Amer A et al. (2017) Somatic Mutations Activating the mTOR Pathway in Dorsal Telencephalic Progenitors Cause a Continuum of Cortical Dysplasias. Cell Rep 21:3754-3766
Woodworth, Mollie B; Girskis, Kelly M; Walsh, Christopher A (2017) Building a lineage from single cells: genetic techniques for cell lineage tracking. Nat Rev Genet 18:230-244
Lodato, Michael A; Rodin, Rachel E; Bohrson, Craig L et al. (2017) Aging and neurodegeneration are associated with increased mutations in single human neurons. Science :
McConnell, Michael J; Moran, John V; Abyzov, Alexej et al. (2017) Intersection of diverse neuronal genomes and neuropsychiatric disease: The Brain Somatic Mosaicism Network. Science 356:
Lim, Elaine T; Uddin, Mohammed; De Rubeis, Silvia et al. (2017) Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder. Nat Neurosci 20:1217-1224
Lodato, Michael A; Woodworth, Mollie B; Lee, Semin et al. (2015) Somatic mutation in single human neurons tracks developmental and transcriptional history. Science 350:94-98
D'Gama, Alissa M; Pochareddy, Sirisha; Li, Mingfeng et al. (2015) Targeted DNA Sequencing from Autism Spectrum Disorder Brains Implicates Multiple Genetic Mechanisms. Neuron 88:910-917