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    oFlowSeq: a quantitative approach to identify protein coding mutations affecting cell type enrichment using mosaic CRISPR-Cas9 edited cerebral organoids

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    Authors
    Dawes, Pepper
    Murray, Liam F
    Olson, Meagan N
    Barton, Nathaniel J
    Smullen, Molly
    Suresh, Madhusoodhanan
    Yan, Guang
    Zhang, Yucheng
    Fernandez-Fontaine, Aria
    English, Jay
    Uddin, Mohammed
    Pak, ChangHui
    Church, George M
    Chan, Yingleong
    Lim, Elaine T
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    UMass Chan Affiliations
    Molecular, Cell and Cancer Biology
    Neurology
    NeuroNexus Institute
    Program in Bioinformatics and Integrative Biology
    Document Type
    Journal Article
    Publication Date
    2023-03-06
    
    Metadata
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    Link to Full Text
    https://doi.org/10.1007/s00439-023-02534-4
    Abstract
    Cerebral organoids are comprised of diverse cell types found in the developing human brain, and can be leveraged in the identification of critical cell types perturbed by genetic risk variants in common, neuropsychiatric disorders. There is great interest in developing high-throughput technologies to associate genetic variants with cell types. Here, we describe a high-throughput, quantitative approach (oFlowSeq) by utilizing CRISPR-Cas9, FACS sorting, and next-generation sequencing. Using oFlowSeq, we found that deleterious mutations in autism-associated gene KCTD13 resulted in increased proportions of Nestin+ cells and decreased proportions of TRA-1-60+ cells within mosaic cerebral organoids. We further identified that a locus-wide CRISPR-Cas9 survey of another 18 genes in the 16p11.2 locus resulted in most genes with > 2% maximum editing efficiencies for short and long indels, suggesting a high feasibility for an unbiased, locus-wide experiment using oFlowSeq. Our approach presents a novel method to identify genotype-to-cell type imbalances in an unbiased, high-throughput, quantitative manner.
    Source
    Dawes P, Murray LF, Olson MN, Barton NJ, Smullen M, Suresh M, Yan G, Zhang Y, Fernandez-Fontaine A, English J, Uddin M, Pak C, Church GM, Chan Y, Lim ET. oFlowSeq: a quantitative approach to identify protein coding mutations affecting cell type enrichment using mosaic CRISPR-Cas9 edited cerebral organoids. Hum Genet. 2023 Mar 6. doi: 10.1007/s00439-023-02534-4. Epub ahead of print. PMID: 36877372.
    DOI
    10.1007/s00439-023-02534-4
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/51964
    PubMed ID
    36877372
    Rights
    © 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
    ae974a485f413a2113503eed53cd6c53
    10.1007/s00439-023-02534-4
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