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

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

doi:10.1016/j.cels.2021.08.006

Cited by 53 publications

(77 citation statements)

References 103 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Other well described synthetic lethal cases include RPP25L/RPP25 16 – 18 , CDS2/CDS1 16 (Table 1 ) as well as other high C-score gene pairs, UAP1/UAP1L1 16 , 19 , 20 , SMARC4/SMARC2 16 , 18 , 20 , 21 , and ENO1/ENO2 22 (Supplementary Table S1 ). Comparing with nine other predictions of synthetic lethality 23 – 31 to four larger scale studies of experimental evidences 16 , 19 , 20 , 32 , the high C-score gene pairs demonstrated among the highest number of matches to experiments, even though matches between prediction to experiments remains few (0 to 14.3%, Supplementary Table S2 ). This result indicate identification of buffering and synthetic lethality is non-trivial, possibly due to a wide variety of biological mechanisms, and the CEBU concept may be one of these mechanisms.…”

Section: Resultsmentioning

confidence: 97%

Functional buffering via cell-specific gene expression promotes tissue homeostasis and cancer robustness

Lin

Cheng

et al. 2022

Sci Rep

View full text Add to dashboard Cite

Functional buffering that ensures biological robustness is critical for maintaining tissue homeostasis, organismal survival, and evolution of novelty. However, the mechanism underlying functional buffering, particularly in multicellular organisms, remains largely elusive. Here, we proposed that functional buffering can be mediated via expression of buffering genes in specific cells and tissues, by which we named Cell-specific Expression-BUffering (CEBU). We developed an inference index (C-score) for CEBU by computing C-scores across 684 human cell lines using genome-wide CRISPR screens and transcriptomic RNA-seq. We report that C-score-identified putative buffering gene pairs are enriched for members of the same duplicated gene family, pathway, and protein complex. Furthermore, CEBU is especially prevalent in tissues of low regenerative capacity (e.g., bone and neuronal tissues) and is weakest in highly regenerative blood cells, linking functional buffering to tissue regeneration. Clinically, the buffering capacity enabled by CEBU can help predict patient survival for multiple cancers. Our results suggest CEBU as a potential buffering mechanism contributing to tissue homeostasis and cancer robustness in humans.

show abstract

Section: Resultsmentioning

confidence: 97%

Functional buffering via cell-specific gene expression promotes tissue homeostasis and cancer robustness

Lin

Cheng

et al. 2022

Sci Rep

View full text Add to dashboard Cite

show abstract

“…Again, we observe that not all screens can identify members of this complex as essential. In this complex, we don't observe COPS7A and COPS7B as essential in any screen since, as we and others have previously shown, COPS7A and COPS7B are synthetic lethal paralog pairs and they encode alternate, replaceable subunits of the complex, while the other subunits are irreplaceable and are uniformly essential (De Kegel et al, 2021;Dede et al, 2020).…”

Section: False Negatives Are Evident In Essential Protein Complexesmentioning

confidence: 72%

Recovering false negatives in CRISPR fitness screens with JLOE

Dede

Hart

2022

Preprint

View full text Add to dashboard Cite

It is widely accepted that pooled library CRISPR knockout screens offer greater sensitivity and specificity than prior technologies in detecting genes whose disruption leads to fitness defects, a critical step in identifying candidate cancer targets. However, the assumption that CRISPR screens are saturating has been largely untested. Through integrated analysis of screen data in cancer cell lines generated by the Cancer Dependency Map, we show that a typical CRISPR screen has a ~20% false negative rate, in addition to library-specific false negatives. Replicability falls sharply as gene expression decreases, while cancer subtype-specific genes within a tissue show distinct profiles compared to false negatives. Cumulative analyses across tissues improves our understanding of core essential genes and suggest only a small number of lineage-specific essential genes, enriched for transcription factors that define pathways of tissue differentiation. To recover false negatives, we introduce a method, Joint Log Odds of Essentiality (JLOE), which builds on our prior work with BAGEL to selectively rescue the false negatives without an increased false discovery rate.

show abstract

“…Specifically, we found that genes from larger paralog families and genes with a more sequence similar paralog are more likely to be dispensable -presumably because those properties can be linked to increased buffering capacity for paralog loss. We also found that paralogs that originated from a whole genome duplication (WGD) as opposed to a small scale duplication (SSD) were both more likely to be essential at least some of the time, but less likely to be essential all of the time -this could be explained by WGD paralogs being more likely to be synthetic lethal (De Kegel et al, 2021;De Kegel & Ryan, 2019). Having determined that paralog passenger genes are overall more likely to be homozygously deleted in tumors, we next asked whether there are differences in the deletion frequency of paralogs with different properties.…”

Section: Homozygous Deletion Frequency Of Paralog Passengers Is Influ...mentioning

confidence: 84%

“…To identify broadly essential genes from the DepMap CRISPR screens we used the gene dependency scores from (Table S2, (De Kegel et al , 2021)). These gene dependency scores were computed with CERES (Meyers et al , 2017) after filtering out potential multi-targeting single guide RNAs, which disproportionately affect paralog dependency scores.…”

Section: Methodsmentioning

confidence: 99%

Paralog dispensability shapes homozygous deletion patterns in tumor genomes

Kegel

Ryan

2022

Preprint

Self Cite

View full text Add to dashboard Cite

Tumor genomes abound with mutations, including homozygous gene deletions, suggesting that tumors are robust to genetic perturbation. In model organisms and cancer cell lines, paralogs have been shown to contribute substantially to genetic robustness - they are generally more dispensable for growth than singletons. Here, by analyzing copy number profiles of >10,000 tumors, we test the hypothesis that the increased dispensability of paralogs shapes tumor genome evolution. We find that paralogs are more likely to be homozygously deleted and that this cannot be explained by other factors known to influence copy number variation. Furthermore, features that influence paralog dispensability in cancer cell lines correlate with paralog deletion frequency in tumors. Finally, paralogs that are broadly essential in cancer cell lines are less frequently deleted in tumors than non-essential paralogs. Overall our results suggest that homozygous deletions of paralogs are more frequently observed in tumor genomes because paralogs are more dispensable.

show abstract

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

Cited by 53 publications

References 103 publications

Functional buffering via cell-specific gene expression promotes tissue homeostasis and cancer robustness

Functional buffering via cell-specific gene expression promotes tissue homeostasis and cancer robustness

Recovering false negatives in CRISPR fitness screens with JLOE

Paralog dispensability shapes homozygous deletion patterns in tumor genomes

Contact Info

Product

Resources

About