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Identifying cell type specific driver genes in autism-associated copy number loci from cerebral organoids

Lim, Elaine T., Chan, Yingleong, Burns, Mannix J., Guo, Xiaoge, Erdin, Serkan, Tai, Derek J.C., Reichert, Julia M., Chan, Ying Kai, Chiang, Jessica J., Meyers, Katharina, Zhang, Xiaochang, Walsh, Christopher A., Yankner, Bruce A., Raychaudhuri, Soumya, Hirschhorn, Joel N., Gusella, James F., Talkowski, Michael E., Church, George M.·2020
DOI 10.1101/2020.11.15.375386

Preprint — published as 10.1038/s41467-022-30968-3

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Abstract

Neuropsychiatric and neurodevelopmental disorders have been particularly challenging to study using animal models, and recently, human-derived cerebral organoids demonstrate great promise for discovering molecular processes that are important in these disorders. However, several challenges remain in achieving robust phenotyping to discover cell type specific genes. We perform RNA sequencing on 71 samples comprising of 1,420 cerebral organoids from 25 donors, and describe a framework (Orgo-Seq) to identify cell type specific driver genes, for 16p11.2 deletions and 15q11-13 duplications. We identify neuroepithelial cells as critical cell types for 16p11.2 deletions, and discover novel and previously reported cell type specific driver genes. Finally, we validated our results that mutations in KCTD13 in the 16p11.2 locus lead to imbalances in the proportion of neuroepithelial cells, using CRISPR/Cas9-edited mosaic organoids. Our work presents a quantitative discovery and validation framework for identifying cell type specific driver genes associated with complex diseases using cerebral organoids.

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Fig. 2 Expression of the gene products in the 16p11.2 and 15q11-13 loci. All data were analyzed from 71 bRNA-seq samples over 25 donors. A Heatmap representation of the normalized expression (FPKM) for all samples across the 22 genes in the 16p11.2 locus. The fold change is represented as a greenyellow heatmap. An asterisk on the ' Fold Change ' heatmap indicates significant differential expression of the gene with FDR ≤ 0.05. B Heatmap representation of the normalized expression (FPKM) for all samples across the 13 genes in the 15q11 -13 locus. The fold change is represented as a greenyellow heatmap. An asterisk on the ' Fold Change ' heatmap indicates significant differential expression of the gene with FDR ≤ 0.05.
Fig. 2 Expression of the gene products in the 16p11.2 and 15q11-13 loci. All data were analyzed from 71 bRNA-seq samples over 25 donors. A Heatmap representation of the normalized expression (FPKM) for all samples across the 22 genes in the 16p11.2 locus. The fold change is represented as a greenyellow heatmap. An asterisk on the ' Fold Change ' heatmap indicates significant differential expression of the gene with FDR ≤ 0.05. B Heatmap representation of the normalized expression (FPKM) for all samples across the 13 genes in the 15q11 -13 locus. The fold change is represented as a greenyellow heatmap. An asterisk on the ' Fold Change ' heatmap indicates significant differential expression of the gene with FDR ≤ 0.05.CC-BY · From the PDF
Fig. 3 Prioritized critical cell types for the 16p11.2 and 15q11-13 loci. All data were analyzed from 71 bRNA-seq samples across 25 donors. A CellScore results with one-sided tests for 16p11.2 (Quadrato dataset 1 ); clusters with FWER ≤ 0.1 in pink adjusted for multiple comparisons. B CellScore results with one-sided tests for 16p11.2 (Tanaka dataset 19 ); clusters with FWER ≤ 0.1 in pink adjusted for multiple comparisons. C CellScore results with one-sided tests for 15q11 -13 (Quadrato dataset 1 ). D CellScore results with one-sided tests for 15q11 -13 (Tanaka dataset 19 ). E Fine-mapping identities of critical cell types for 16p11.2 (Eze dataset 20 ); sizes of the circles represent mean gene overlaps between cell type clusters. F Fine-mapping identities of critical cell types for 16p11.2 (Velasco dataset 13 ); sizes of the circles represent mean gene overlaps between cell type clusters. G GeneScore results for 16p11.2 (Quadrato dataset 1 ). H GeneScore results for 16p11.2 (Tanaka dataset 19 ).
Fig. 3 Prioritized critical cell types for the 16p11.2 and 15q11-13 loci. All data were analyzed from 71 bRNA-seq samples across 25 donors. A CellScore results with one-sided tests for 16p11.2 (Quadrato dataset 1 ); clusters with FWER ≤ 0.1 in pink adjusted for multiple comparisons. B CellScore results with one-sided tests for 16p11.2 (Tanaka dataset 19 ); clusters with FWER ≤ 0.1 in pink adjusted for multiple comparisons. C CellScore results with one-sided tests for 15q11 -13 (Quadrato dataset 1 ). D CellScore results with one-sided tests for 15q11 -13 (Tanaka dataset 19 ). E Fine-mapping identities of critical cell types for 16p11.2 (Eze dataset 20 ); sizes of the circles represent mean gene overlaps between cell type clusters. F Fine-mapping identities of critical cell types for 16p11.2 (Velasco dataset 13 ); sizes of the circles represent mean gene overlaps between cell type clusters. G GeneScore results for 16p11.2 (Quadrato dataset 1 ). H GeneScore results for 16p11.2 (Tanaka dataset 19 ).CC-BY · From the PDF
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Authors
Lim, E. T., Chan, Y., Burns, M. J., Guo, X., Erdin, S., Tai, D. J. C., Reichert, J. M., Chan, Y. K., Chiang, J. J., Meyers, K., Zhang, X., Walsh, C. A., Yankner, B. A., Raychaudhuri, S., Hirschhorn, J. N., Gusella, J. F., Talkowski, M. E., & Church, G. M.
Publisher
openRxiv
Published
2020-11-17
DOI
10.1101/2020.11.15.375386
Cited by
2
References
1
Type
Preprint
Licence
www.biorxiv.org/about/FAQ#license (vor)

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