Comprehensive prediction of robust synthetic lethality between paralog pairs in cancer cell lines.

Barbara De Kegel,David J Adams,Niall Quinn,Nicola A Thompson,Colm J Ryan

doi:10.1016/j.cels.2021.08.006

Barbara De Kegel, David J Adams + Show 3 more

Open Access

https://doi.org/10.1016/j.cels.2021.08.006

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Abstract

Pairs of paralogs may share common functionality and, hence, display synthetic lethal interactions. As the majority of human genes have an identifiable paralog, exploiting synthetic lethality between paralogs may be a broadly applicable approach for targeting gene loss in cancer. However, only a biased subset of human paralog pairs has been tested for synthetic lethality to date. Here, by analyzing genome-wide CRISPR screens and molecular profiles of over 700 cancer cell lines, we identify features predictive of synthetic lethality between paralogs, including shared protein-protein interactions and evolutionary conservation. We develop a machine-learning classifier based on these features to predict which paralog pairs are most likely to be synthetic lethal and to explain why. We show that our classifier accurately predicts the results of combinatorial CRISPR screens in cancer cell lines and furthermore can distinguish pairs that are synthetic lethal in multiple cell lines from those that are cell-line specific. A record of this paper's transparent peer review process is included in the supplemental information.

Highlights

Gene duplication is the primary means by which new genes are created (Zhang, 2003), and the majority of human genes are duplicates (Zerbino et al, 2018)
Indirect evidence for the contribution of paralog buffering to genetic robustness is provided by the finding that, in both model organisms and cancer cell lines, paralog genes are less likely to be essential than genes with no identifiable paralogs (Blomen et al, 2015; Dandage and Landry, 2019; De Kegel and Ryan, 2019; Gu et al, 2003; Wang et al 2015)
We find that paralog pairs that function in largely essential protein complexes or that have protein-protein interactions with essential genes are more likely to be synthetic lethal (SL) (Figure 3A)

Summary

Introduction

Gene duplication is the primary means by which new genes are created (Zhang, 2003), and the majority of human genes are duplicates (paralogs) (Zerbino et al, 2018). Paralog pairs may functionally diverge over time, many maintain at least some functional overlap, even after long evolutionary periods (Conant and Wolfe, 2008; Vavouri et al, 2009) This functional overlap may allow paralog pairs to buffer each other’s loss, contributing to the overall ability of cells and organisms to tolerate genetic perturbations. Synthetic lethal relationships appear to be much more frequent among paralog pairs than other gene pairs—in the budding yeast Saccharomyces cerevisiae, where comprehensive double perturbation screens have been performed, 25%–35% of paralog pairs are synthetic lethal, compared with

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