A genome wide dosage suppressor network reveals genomic robustness

Abstract

Genomic robustness is the extent to which an organism has evolved to withstand the effects of deleterious mutations. We explored the extent of genomic robustness in budding yeast by genome wide dosage suppressor analysis of 53 conditional lethal mutations in cell division cycle and RNA synthesis related genes, revealing 660 suppressor interactions of which 642 are novel. This collection has several distinctive features, including high co-occurrence of mutant-suppressor pairs within protein modules, highly correlated functions between the pairs and higher diversity of functions among the co-suppressors than previously observed. Dosage suppression of essential genes encoding RNA polymerase subunits and chromosome cohesion complex suggests a surprising degree of functional plasticity of macromolecular complexes, and the existence of numerous degenerate pathways for circumventing the effects of potentially lethal mutations. These results imply that organisms and cancer are likely able to exploit the genomic robustness properties, due the persistence of cryptic gene and pathway functions, to generate variation and adapt to selective pressures.

Mechanisms of suppression: The wiring of genetic resilience

“…B and C). This mechanistic class is equally prevalent in dosage and genomic suppression datasets, and explains ∼2–6% of all unbiased suppression interactions mapped in yeast (Table ) . In the case of loss‐of‐function suppressor mutations, the suppressor gene often has antagonistic effects compared to the query gene.…”

“…The mechanisms by which increased protein synthesis could cause suppression are less obvious. Genes encoding ribosomal subunits are often found as dosage suppressors , but it seems unlikely that overexpression of a single subunit of the ribosome could lead to increased translation. In apparent contrast, partial knockdown of ribosomal subunits can rescue a variety of mutant phenotypes in the worm Caenorhabditis elegans .…”

“…Similarly, dosage suppression can occasionally (2–4% of all interactions) be achieved by overexpression of a chaperone that stabilizes the query mutant protein, and thus enlarges the pool of active query protein (Fig. C, Table ) .…”

Understanding Huntington's disease using Machine Learning Approaches

“…(Patra et al, 2017) These findings led us to hypothesize whether overexpression of smc2-8 suppressors could suppress mHtt toxicity (Figure 3.7). As a test of this hypothesis, we examined if a set of suppressors of smc2-8 mutation (including SMC2), and a selected set of cohesin/condensin genes could suppress mHtt toxicity in yeast.…”

“…Previous studies with these interaction datasets did not reveal a noteworthy enrichment of chromosome condensation or DNA damage response pathways among suppressors or enhancers of mHtt toxicity. We have recently generated a large collection of gene-dosage suppressors of lethal mutations in yeast (Patra et al, 2017), which presented an opportunity to ask whether there might be any indirect connection between suppressors of chromosome condensation defects and genes known to modify mHtt toxicity.…”