Transcriptional linkage analysis with in vivo AAV-Perturb-seq

Antonio J. Santinha, Esther Klingler, Maria Kuhn, Rick Farouni, Sandra Lagler, Georgios Kalamakis, Ulrike Lischetti, Denis Jabaudon and Randall J. Platt ()
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Antonio J. Santinha: ETH Zurich
Esther Klingler: University of Geneva
Maria Kuhn: ETH Zurich
Rick Farouni: ETH Zurich
Sandra Lagler: ETH Zurich
Georgios Kalamakis: ETH Zurich
Ulrike Lischetti: ETH Zurich
Denis Jabaudon: University of Geneva
Randall J. Platt: ETH Zurich

Nature, 2023, vol. 622, issue 7982, 367-375

Abstract: Abstract The ever-growing compendium of genetic variants associated with human pathologies demands new methods to study genotype–phenotype relationships in complex tissues in a high-throughput manner1,2. Here we introduce adeno-associated virus (AAV)-mediated direct in vivo single-cell CRISPR screening, termed AAV-Perturb-seq, a tuneable and broadly applicable method for transcriptional linkage analysis as well as high-throughput and high-resolution phenotyping of genetic perturbations in vivo. We applied AAV-Perturb-seq using gene editing and transcriptional inhibition to systematically dissect the phenotypic landscape underlying 22q11.2 deletion syndrome3,4 genes in the adult mouse brain prefrontal cortex. We identified three 22q11.2-linked genes involved in known and previously undescribed pathways orchestrating neuronal functions in vivo that explain approximately 40% of the transcriptional changes observed in a 22q11.2-deletion mouse model. Our findings suggest that the 22q11.2-deletion syndrome transcriptional phenotype found in mature neurons may in part be due to the broad dysregulation of a class of genes associated with disease susceptibility that are important for dysfunctional RNA processing and synaptic function. Our study establishes a flexible and scalable direct in vivo method to facilitate causal understanding of biological and disease mechanisms with potential applications to identify genetic interventions and therapeutic targets for treating disease.

Date: 2023
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DOI: 10.1038/s41586-023-06570-y

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