Complex topology rather than complex membership is a determinant of protein dosage sensitivity

The 'balance hypothesis' predicts that non-stoichiometric variations in concentrations of proteins participating in complexes should be deleterious. As a corollary, heterozygous deletions and overexpression of protein complex members should have measurable fitness effects. However, genome-wide studies of heterozygous deletions in Saccharomyces cerevisiae and overexpression have been unable to unambiguously relate complex membership to dosage sensitivity. We test the hypothesis that it is not complex membership alone but rather the topology of interactions within a complex that is a predictor of dosage sensitivity. We develop a model that uses the law of mass action to consider how complex formation might be affected by varying protein concentrations given a protein's topological positioning within the complex. Although we find little evidence for combinatorial inhibition of complex formation playing a major role in overexpression phenotypes, consistent with previous results, we show significant correlations between predicted sensitivity of complex formation to protein concentrations and both heterozygous deletion fitness and protein abundance noise levels. Our model suggests a mechanism for dosage sensitivity and provides testable predictions for the effect of alterations in protein abundance noise.