Chou Juihsuan, Anvar Nazanin Esmaeili, Elghaish Reem, Chen Junjie, Hart Traver
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
The UT Health/MD Anderson Graduate School of Biological Sciences, Houston, Texas.
bioRxiv. 2024 Aug 20:2024.08.19.608665. doi: 10.1101/2024.08.19.608665.
Synthetic lethality offers a promising strategy for cancer treatment by targeting genetic vulnerabilities unique to tumor cells, leading to selective tumor cell death. However, single-gene knockout screens often miss functional redundancy due to paralog genes. Multiplex CRISPR systems, including various Cas9 and Cas12a platforms, have been developed to assay genetic interactions, yet no systematic comparison of method to identify synthetic lethality from CRISPR screens has been conducted.
We evaluated data from four in4mer CRISPR/Cas12a screens in cancer cell lines, using three bioinformatic approaches to identify synthetic lethal interactions: delta log fold change (dLFC), Z-transformed dLFC (ZdLFC), and rescaled dLFC (RdLFC). Both ZdLFC and RdLFC provided more consistent identification of synthetic lethal pairs across cell lines compared to the unscaled dLFC method.
The ZdLFC method offers a robust framework for scoring synthetic lethal interactions from paralog screens, providing consistent results across different cell lines without requiring a training set of known positive interactors.
合成致死性通过靶向肿瘤细胞特有的基因脆弱性提供了一种很有前景的癌症治疗策略，从而导致选择性肿瘤细胞死亡。然而，单基因敲除筛选由于旁系同源基因常常会遗漏功能冗余。包括各种Cas9和Cas12a平台在内的多重CRISPR系统已被开发用于分析基因相互作用，但尚未对从CRISPR筛选中识别合成致死性的方法进行系统比较。
我们评估了来自癌细胞系中四个信息性CRISPR/Cas12a筛选的数据，使用三种生物信息学方法来识别合成致死相互作用：对数变化倍数差值（dLFC）、Z变换dLFC（ZdLFC）和重新缩放的dLFC（RdLFC）。与未缩放的dLFC方法相比，ZdLFC和RdLFC在跨细胞系中对合成致死对的识别更为一致。
ZdLFC方法为从旁系同源筛选中对合成致死相互作用进行评分提供了一个强大的框架，在不同细胞系中提供一致的结果，而无需已知阳性相互作用体的训练集。
