Scalable genetic screening for regulatory circuits using compressed Perturb-seq.
Scalable genetic screening for regulatory circuits using compressed Perturb-seq.
复制标题
使用压缩的 Perturb-seq 对调节电路进行可扩展的遗传筛查。
DOI：
10.1038/s41587-023-01964-9
复制
发表时间：
2023
影响因子：
46.9
通讯作者：
Cleary,Brian
中科院分区：
文献类型：
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作者：
Yao,Douglas;Binan,Loic;Bezney,Jon;Simonton,Brooke;Freedman,Jahanara;Frangieh,ChrisJ;Dey,Kushal;Geiger-Schuller,Kathryn;Eraslan,Basak;Gusev,Alexander;Regev,Aviv;Cleary,Brian
Pooled CRISPR screens with single-cell RNA sequencing readout (Perturb-seq) have emerged as a key technique in functional genomics, but they are limited in scale by cost and combinatorial complexity. In this study, we modified the design of Perturb-seq by incorporating algorithms applied to random, low-dimensional observations. Compressed Perturb-seq measures multiple random perturbations per cell or multiple cells per droplet and computationally decompresses these measurements by leveraging the sparse structure of regulatory circuits. Applied to 598 genes in the immune response to bacterial lipopolysaccharide, compressed Perturb-seq achieves the same accuracy as conventional Perturb-seq with an order of magnitude cost reduction and greater power to learn genetic interactions. We identified known and novel regulators of immune responses and uncovered evolutionarily constrained genes with downstream targets enriched for immune disease heritability, including many missed by existing genome-wide association studies. Our framework enables new scales of interrogation for a foundational method in functional genomics.
