| First Author | Santinha AJ | Year | 2023 |
| Journal | Nature | Volume | 622 |
| Issue | 7982 | Pages | 367-375 |
| PubMed ID | 37730998 | Mgi Jnum | J:371220 |
| Mgi Id | MGI:7647076 | Doi | 10.1038/s41586-023-06570-y |
| Citation | Santinha AJ, et al. (2023) Transcriptional linkage analysis with in vivo AAV-Perturb-seq. Nature 622(7982):367-375 |
| abstractText | 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 manner(1,2). 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 syndrome(3,4) 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. |
