Abstract

Understanding how changes in DNA are propagated through biomolecules and interactions to give rise to phenotypic diversity is an important objective for evolutionary biology. To contribute to this goal we used a comparative approach to study the evolution of post-translational and chemical-genetic networks.

Protein function is highly regulated by post-translational modifications (PTMs) but little is known about the evolution of these regulatory networks. Using mass-spectrometry we characterized the in-vivo phosphoproteomes of three fungal species. We observed that kinase networks diverge at a fast rate although the average phosphorylation level of functional modules (i.e. complexes and pathways) is well conserved. To study the importance of the observed variation we curated over 200.000 published PTMs for 11 species and developed approaches to predict their function. Our analysis suggests that there are a significant number of non-functional modifications as well as potential routes for neutral variation of these regulatory interactions.

In parallel we performed a chemical genetic screen to measure the functional interactions between genes and small-molecules in S. cerevisiae and S. pombe. In analogy to the observations made for the PTM networks, drug-module interactions were found to diverge slower than drug-gene interactions. Importantly, data from both species could be combined to improve the prediction of the mode-of-action of the tested compounds.

These interaction networks offer us a glimpse into how genotypes are translated to phenotypes and we envision that they will increasingly be used in interpreting the consequences of genetic variation occurring within populations as well as in the rational design of combinatorial therapeutics.