Integrated single-cell and functional analysis of Dup15q syndrome

  • Awarded: 2019
  • Award Type: Research
  • Award #: 632842

Autism spectrum disorder (ASD) is a major global health concern, affecting 1 in 59 children in the United States. Currently, no effective drug treatment targeting core ASD pathology and symptoms exists. Lack of targeted therapy is, in large part, due to gaps in our understanding of the specific cell types and neuronal circuits affected by ASD.

Single-cell genomic technologies have revolutionized approaches to studying the cellular heterogeneity of the human brain. A recent study by Arnold Kriegstein, Dmitry Velmeshev and colleagues at the University of California, San Francisco used single-nucleus RNA sequencing to analyze postmortem brain tissue from individuals with idiopathic ASD1. Partially funded by a SFARI Pilot Award, this study demonstrated that autism-specific molecular pathology preferentially affects upper-layer cortical projection neurons. However, ASD is extremely heterogeneous in terms of underlying genetics. Additionally, studying postmortem tissue samples alone is not sufficient to elucidate the mechanisms of disease pathogenesis. To overcome these limitations, Kriegstein’s team now plans to focus on the genetic syndrome most commonly associated with ASD: chromosome 15q11.2-13.1 duplication (Dup15q) syndrome.

Kriegstein and colleagues propose to first perform single-nucleus RNA sequencing analysis of postmortem brain tissue samples from individuals with Dup15q to identify disease-associated transcriptional changes in specific cell types and to compare them to the previous observations in idiopathic ASD. Then, the team will utilize Dup15q-derived induced pluripotent (iPS) cells to generate cerebral organoids and will characterize their development with single-cell RNA sequencing and functional assays. Combining these approaches will allow for the identification of cell type-specific changes in Dup15q syndrome that manifest as specific neural lineages differentiate and mature. Finally, upper-layer projection neurons from Dup15q iPS cells and neurotypical control lines will be generated and transplanted into mouse neocortex. The researchers will then use electrophysiological recordings to assess how these Dup15q-derived neurons functionally integrate into neuronal circuitry. Taken together, findings from these studies will allow for the dissection of cell-type-specific mechanisms of ASD in the context of a genetically defined syndrome.


1.Velmeshev D. et al. Science 364, 685-689 (2019) PubMed
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