Discovery of synthetic lethal and tumor suppressive paralog pairs in the human genome
Ontology highlight
ABSTRACT:
ORGANISM(S): synthetic construct Homo sapiens
PROVIDER: GSE178179 | GEO | 2021/08/31
REPOSITORIES: GEO
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Project description:Activating mutations in RAS GTPases drive one fifth of cancers, but poor understandings of many RAS effectors and regulators, and of the roles of their different paralogs, continue to impede drug development. We developed a multi-stage discovery and screening process to understand RAS function and identify RAS-related susceptibilities in lung adenocarcinoma. Using affinity purification mass spectrometry (AP/MS), we generated a protein-protein interaction map of the RAS pathway containing thousands of interactions. From this network we constructed a CRISPR dual knockout library targeting 119 RAS-related genes that we screened for genetic interactions (GIs). We found important new effectors of RAS-driven cellular functions, RADIL and the GEF RIN1, and over 250 synthetic lethal GIs, including a potent KRAS-dependent interaction between RAP1GDS1 and RHOA. Many GIs link specific paralogs within and between gene families. These findings illustrate the power of the multiomic approach to identify synthetic lethal combinations for hitherto undruggable cancers.
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Project description:Chromatin regulators are frequently mutated in human cancer and are attractive drug targets. They include diverse proteins that share functional domains and assemble into related multi-subunit complexes. To investigate functional relationships among these regulators, here we apply combinatorial CRISPR knockouts (KOs) to test over 35,000 gene-gene pairings in leukemia cells, using a library of over 300,000 constructs. Top pairs that demonstrate either compensatory non-lethal interactions or synergistic lethality enrich for paralogs and targets that occupy the same protein complex. The screen highlights protein complex dependencies not apparent in single KO screens, for example MCM histone exchange, the nucleosome remodeling and deacetylase (NuRD) complex, and HBO1 (KAT7) complex. We explore two approaches to NuRD complex inactivation. Paralog and non-paralog combinations of the KAT7 complex emerge as synergistic lethal and specifically nominate the ING5 PHD domain as a potential therapeutic target when paired with other KAT7 complex member losses. These findings highlight the power of combinatorial screening to provide mechanistic insight and identify therapeutic targets within redundant networks.
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Project description:This study measured the rates at which duplicated genes in the Daphnia pulex genome diverge in function, based on significant differences in their gene expression when paralogs of various ages were tested across 8 to 12 contrasting conditions. The conditions were designated A to L. The number and diversity of experiments were designed to uncover condition specific expression. The age of duplicated genes was measured as the level of silent-site nucleotide substitution (Ks) between paralogs. Two methods were used to evaluate the degree to which expression pattern of paralogs differ. (1) The first method investigated variation in the differential expression patterns among duplicates of individual gene families by calculating the M values (log2 treatment – log2 reference) from eight experiments, then calculating Pearson correlations. (2) The second method is a global investigation which defined a distinguishable expression pattern by a significance criterion (p < 0.05) using ANOVA for the simple statistical model of aov( Yab ~ Xab ), for matrices Yab differential expression M values and Xab gene factors, with replicates. We used pr(M) < 0.05 as criterion that expression differs between paralog genes, for zero to twelve treatments. The hypothesis that is tested is one of how many paralog pairs in each Ks category reach the criterion of a distinguishable expression pattern, which is tested for significance with Fisher's exact test for count data. This method is reliable for as few as two probes for one gene and one probe for the other, although a greater number of replicate probes produced more significant results. We compared the gene expression patterns for condition 1 versus condition 2 using four to six biological replicates, including balanced dye-swaps. All probes including random probes were quantile-normalized across chips, subarrays, samples and replicates.
2011-02-01 | E-GEOD-25850 | biostudies-arrayexpress
Project description:This study measured the rates at which duplicated genes in the Daphnia pulex genome diverge in function, based on significant differences in their gene expression when paralogs of various ages were tested across 8 to 12 contrasting conditions. The conditions were designated A to L. The number and diversity of experiments were designed to uncover condition specific expression. The age of duplicated genes was measured as the level of silent-site nucleotide substitution (Ks) between paralogs. Two methods were used to evaluate the degree to which expression pattern of paralogs differ. (1) The first method investigated variation in the differential expression patterns among duplicates of individual gene families by calculating the M values (log2 treatment – log2 reference) from eight experiments, then calculating Pearson correlations. (2) The second method is a global investigation which defined a distinguishable expression pattern by a significance criterion (p < 0.05) using ANOVA for the simple statistical model of "aov( Yab ~ Xab )", for matrices Yab differential expression M values and Xab gene factors, with replicates. We used pr(M) < 0.05 as criterion that expression differs between paralog genes, for zero to twelve treatments. The hypothesis that is tested is one of how many paralog pairs in each Ks category reach the criterion of a distinguishable expression pattern, which is tested for significance with Fisher's exact test for count data. This method is reliable for as few as two probes for one gene and one probe for the other, although a greater number of replicate probes produced more significant results. We compared the gene expression patterns for condition 1 versus condition 2 using four to six biological replicates, including balanced dye-swaps. All probes including random probes were quantile-normalized across chips, subarrays, samples and replicates.
2011-02-01 | E-GEOD-25845 | biostudies-arrayexpress
Project description:This study measured the rates at which duplicated genes in the Daphnia pulex genome diverge in function, based on significant differences in their gene expression when paralogs of various ages were tested across 8 to 12 contrasting conditions. The conditions were designated A to L. The number and diversity of experiments were designed to uncover condition specific expression. The age of duplicated genes was measured as the level of silent-site nucleotide substitution (Ks) between paralogs. Two methods were used to evaluate the degree to which expression pattern of paralogs differ. (1) The first method investigated variation in the differential expression patterns among duplicates of individual gene families by calculating the M values (log2 treatment – log2 reference) from eight experiments, then calculating Pearson correlations. (2) The second method is a global investigation which defined a distinguishable expression pattern by a significance criterion (p < 0.05) using ANOVA for the simple statistical model of aov( Yab ~ Xab ), for matrices Yab differential expression M values and Xab gene factors, with replicates. We used pr(M) < 0.05 as criterion that expression differs between paralog genes, for zero to twelve treatments. The hypothesis that is tested is one of how many paralog pairs in each Ks category reach the criterion of a distinguishable expression pattern, which is tested for significance with Fisher's exact test for count data. This method is reliable for as few as two probes for one gene and one probe for the other, although a greater number of replicate probes produced more significant results. We compared the gene expression patterns for condition 1 versus condition 2 using four to six biological replicates, including balanced dye-swaps. All probes including random probes were quantile-normalized across chips, subarrays, samples and replicates.
2011-02-01 | E-GEOD-25851 | biostudies-arrayexpress
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2011-02-01 | E-GEOD-25841 | biostudies-arrayexpress
Project description:This study measured the rates at which duplicated genes in the Daphnia pulex genome diverge in function, based on significant differences in their gene expression when paralogs of various ages were tested across 8 to 12 contrasting conditions. The conditions were designated A to L. The number and diversity of experiments were designed to uncover condition specific expression. The age of duplicated genes was measured as the level of silent-site nucleotide substitution (Ks) between paralogs. Two methods were used to evaluate the degree to which expression pattern of paralogs differ. (1) The first method investigated variation in the differential expression patterns among duplicates of individual gene families by calculating the M values (log2 treatment – log2 reference) from eight experiments, then calculating Pearson correlations. (2) The second method is a global investigation which defined a distinguishable expression pattern by a significance criterion (p < 0.05) using ANOVA for the simple statistical model of aov( Yab ~ Xab ), for matrices Yab differential expression M values and Xab gene factors, with replicates. We used pr(M) < 0.05 as criterion that expression differs between paralog genes, for zero to twelve treatments. The hypothesis that is tested is one of how many paralog pairs in each Ks category reach the criterion of a distinguishable expression pattern, which is tested for significance with Fisher's exact test for count data. This method is reliable for as few as two probes for one gene and one probe for the other, although a greater number of replicate probes produced more significant results. We compared the gene expression patterns for condition 1 versus condition 2 using four to six biological replicates, including balanced dye-swaps. All probes including random probes were quantile-normalized across chips, subarrays, samples and replicates.
2011-02-01 | E-GEOD-25843 | biostudies-arrayexpress
Project description:This study measured the rates at which duplicated genes in the Daphnia pulex genome diverge in function, based on significant differences in their gene expression when paralogs of various ages were tested across 8 to 12 contrasting conditions. The conditions were designated A to L. The number and diversity of experiments were designed to uncover condition specific expression. The age of duplicated genes was measured as the level of silent-site nucleotide substitution (Ks) between paralogs. Two methods were used to evaluate the degree to which expression pattern of paralogs differ. (1) The first method investigated variation in the differential expression patterns among duplicates of individual gene families by calculating the M values (log2 treatment – log2 reference) from eight experiments, then calculating Pearson correlations. (2) The second method is a global investigation which defined a distinguishable expression pattern by a significance criterion (p < 0.05) using ANOVA for the simple statistical model of aov( Yab ~ Xab ), for matrices Yab differential expression M values and Xab gene factors, with replicates. We used pr(M) < 0.05 as criterion that expression differs between paralog genes, for zero to twelve treatments. The hypothesis that is tested is one of how many paralog pairs in each Ks category reach the criterion of a distinguishable expression pattern, which is tested for significance with Fisher's exact test for count data. This method is reliable for as few as two probes for one gene and one probe for the other, although a greater number of replicate probes produced more significant results.
2011-02-01 | GSE25850 | GEO
Project description:This study measured the rates at which duplicated genes in the Daphnia pulex genome diverge in function, based on significant differences in their gene expression when paralogs of various ages were tested across 8 to 12 contrasting conditions. The conditions were designated A to L. The number and diversity of experiments were designed to uncover condition specific expression. The age of duplicated genes was measured as the level of silent-site nucleotide substitution (Ks) between paralogs. Two methods were used to evaluate the degree to which expression pattern of paralogs differ. (1) The first method investigated variation in the differential expression patterns among duplicates of individual gene families by calculating the M values (log2 treatment – log2 reference) from eight experiments, then calculating Pearson correlations. (2) The second method is a global investigation which defined a distinguishable expression pattern by a significance criterion (p < 0.05) using ANOVA for the simple statistical model of "aov( Yab ~ Xab )", for matrices Yab differential expression M values and Xab gene factors, with replicates. We used pr(M) < 0.05 as criterion that expression differs between paralog genes, for zero to twelve treatments. The hypothesis that is tested is one of how many paralog pairs in each Ks category reach the criterion of a distinguishable expression pattern, which is tested for significance with Fisher's exact test for count data. This method is reliable for as few as two probes for one gene and one probe for the other, although a greater number of replicate probes produced more significant results.
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