A splicing code for elucidating genetic and molecular mechanisms underlying autism

  • Awarded: 2021
  • Award Type: Targeted: Genomics of ASD: Pathways to Genetic Therapies
  • Award #: 893981

Alternative splicing generates transcript variants from over 90 percent of human genes, and its disruption causes or contributes to numerous diseases and disorders. Benjamin Blencowe’s laboratory previously discovered and characterized a highly conserved alternative splicing regulatory network comprising a few hundred 3–27 nucleotide-long neuronal ‘microexons’ and a ‘master’ activator of these exons, the neuronal-specific Ser/Arg-repeat protein nSR100/SRRM41. This network was found to be disrupted in approximately one-third of analyzed individuals diagnosed with autism spectrum disorder (ASD).

Supporting a role for misregulation of this network in ASD are the following observations: (a) neuronal microexons are enriched in genes with critical functions associated with neurogenesis and synaptic biology; (b) genome-wide CRISPR-based screens have identified sets of approximately 200 hundred genes associated with microexon regulation that are also enriched in ASD-linked variants2; and (c) mice haploinsufficient for SRRM43 or harboring deletions of individual microexons4 display altered social behaviors and other phenotypes relevant for ASD. Collectively, these studies provide evidence that the neuronal microexon network represents a regulatory ‘hub’ that is commonly impacted — and causally implicated — in ASD. However, the full landscape of neuronal microexons as well as the specific molecular and genetic mechanisms resulting in their disruption are poorly understood. Moreover, the specific functions of the vast majority of microexons, including those disrupted in ASD, are unknown.

These questions form the major goals of this project. Its specific aims are to: (1) systematically discover and characterize neural microexons using a new splicing code tool and extensive bulk and single-cell RNA sequencing analyses; (2) develop a comprehensive resource for predicting the effects of experimental and genetic variation on microexon splicing by integrating information from the code with whole-genome sequencing data from individuals with ASD and other resources; (3) experimentally validate and functionally characterize microexons and associated ASD-linked variants; and (4) integrate results from goals 1–3 in publicly accessible databases. Taken together, these studies are expected to provide new insight into molecular and genetic mechanisms underlying ASD and related neurological conditions.


1.Irimia M. et al. Cell 159, 1511-1523 (2014) PubMed
2.Gonatopoulos-Pournatzis T. et al. Mol. Cell 72, 510-524 (2018) PubMed
3.Quesnel-Vallières M. et al. Mol. Cell 64, 1023-1034 (2016) PubMed
4.Gonatopoulos-Pournatzis T. et al. Mol. Cell 77, 1176-1192 (2020) PubMed
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