Predicting cell-type-specific exon inclusion in the human brain reveals more complex splicing mechanisms in neurons than glia

bioRxiv (Cold Spring Harbor Laboratory)

Abstract

Abstract Alternative splicing contributes to molecular diversity across brain cell types. RNA-binding proteins (RBPs) regulate splicing, but the genome-wide mechanisms remain poorly understood. Here, we used RBP binding sites and/or the genomic sequence to predict exon inclusion in neurons and glia as measured by long-read single-cell data in human hippocampus and frontal cortex. We found that alternative splicing is harder to predict in neurons compared to glia in both brain regions. Comparing neurons and glia, the position of RBP binding sites in alternatively spliced exons in neurons differ more from non-variable exons indicating distinct splicing mechanisms. Model interpretation pinpointed RBPs, including QKI, potentially regulating alternative splicing between neurons and glia. Finally, using our models, we accurately predict and prioritize the effect of splicing QTLs. Taken together, our models provide new insights into the mechanisms regulating cell-type-specific alternative splicing and can accurately predict the effect of genetic variants on splicing.

Authors 7

1. Lieke Michielsen Aachen Department of Human Genetics

   Leiden University Medical Center · Delft University of Technology

   Affiliation as printed

   Delft Bioinformatics Lab, Delft University of Technology, Delft, NL

   Department of Human Genetics, Leiden University Medical Center, Leiden, NL

2. Justine Hsu

   Weill Cornell Medicine

   Affiliation as printed

   Center for Neurogenetics, Brain and Mind Research Institute, Weill Cornell Medicine, NY, USA

3. Anoushka Joglekar

   New York Genome Center · Weill Cornell Medicine

   Affiliation as printed

   Center for Neurogenetics, Brain and Mind Research Institute, Weill Cornell Medicine, NY, USA

   New York Genome Center, New York, NY, USA

4. Natan Belchikov

   Weill Cornell Medicine

   Affiliation as printed

   Center for Neurogenetics, Brain and Mind Research Institute, Weill Cornell Medicine, NY, USA

5. Marcel J. T. Reinders Aachen Department of Human Genetics

   Leiden University Medical Center · Delft University of Technology

   Affiliation as printed

   Delft Bioinformatics Lab, Delft University of Technology, Delft, NL

   Department of Human Genetics, Leiden University Medical Center, Leiden, NL

6. Hagen Tilgner corresponding

   Weill Cornell Medicine

   Affiliation as printed

   Center for Neurogenetics, Brain and Mind Research Institute, Weill Cornell Medicine, NY, USA

7. Ahmed Essam Mahfouz corresponding Aachen Department of Human Genetics

   Leiden University Medical Center · Delft University of Technology

   Affiliation as printed

   Delft Bioinformatics Lab, Delft University of Technology, Delft, NL

   Department of Human Genetics, Leiden University Medical Center, Leiden, NL