Mapping Genetic Interactions of All Paralogs in the Human Genome
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Background
Functionally redundant paralogs in the human genome are the most common source of synthetic lethality (i.e., loss of one paralog conveys dependency to another). However, most paralogs have yet to be experimentally tested and the human paralogome remains largely uncharacterized.
Results
We performed the first pairwise genetic screen of all human paralogs using a multiplexed CRISPR-Cas12 library, which revealed that digenic synthetic lethalities are relatively rare (<0.5% of all paralog pairs) and varied in penetrance across different cancer models. We hypothesized that the variable penetrance of digenic synthetic lethalities was a result of complex polygenic interactions with endogenous factors. A multivariable regression analysis of 1,278 pairs and endogenous cellular features across 30 cancer models revealed that perturbations of related pathways were frequently predictive of paralog synthetic lethality. A machine learning classifier was also built to predict synthetic lethalities using a weighted set of true positives, accounting for the variable penetrance of synthetic lethal interactions. Intuitively, the predictive scores revealed that the penetrance of synthetic lethal interactions was driven by the overlap and essentiality of the protein-protein interactions for each paralog pair.
Conclusions
This study provided a comprehensive analysis of all digenic interactions in the human paralogome, as well as the key features that underlie the heterogeneity in synthetic lethalities that have been reported here and elsewhere.
