Buffering of genetic dominance by allele-specific protein complex assembly

Protein complex assembly often occurs while subunits are being translated, resulting in complexes whose sub-units were translated from the same mRNA in an allele-specific manner. It has thus been hypothesized that such cotranslational assembly may counter the assembly-mediated dominant-negative effect, whereby co-assembly of mutant and wild-type subunits poisons complex activity. Here, we show that cotranslationally assembling subunits are much less likely to be associated with autosomal dominant relative to recessive disorders, and that subunits with dominant-negative disease mutations are significantly depleted in cotranslational assembly com-pared to those associated with loss-of-function mutations. We also find that complexes with known dominant -negative effects tend to expose their interfaces late during translation, lessening the likelihood of cotranslation-al assembly. Finally, by combining complex properties with other features, we trained a computational model for predicting proteins likely to be associated with non-loss-of-function disease mechanisms, which we believe will be of considerable utility for protein variant interpretation.

Automated summary

Protein complex assembly during translation may counteract the dominant-negative effect and is less associated with autosomal dominant disorders and dominant-negative disease mutations. Complexes with known dominant-negative effects tend to expose their interfaces late during translation, reducing the likelihood of cotranslational assembly. A computational model combining complex properties and other features can predict proteins associated with non-loss-of-function disease mechanisms.