Background. Functional constraint through genomic architecture is suggested to be an important dimension of genome evolution, but quantitative evidence for this idea is rare. In this contribution, existing evidence and discussions on genomic architecture as constraint for convergent evolution, rapid adaptation, and genic adaptation are summarized into alternative, testable hypotheses. Network architecture statistics from protein-protein interaction networks are then used to calculate differences in evolutionary outcomes on the example of genomic evolution among yeast, and the results are used to evaluate statistical support for these longstanding hypotheses. Results.A discriminant function analysis lent statistical support to classifying the yeast interactome into hub, intermediate and peripheral nodes based on network neighborhood connectivity, betweenness centrality, and average shortest path length. Quantitative support for the existence of genomic architecture as mechanistic basis for evolutionary constraint is then revealed through utilizing these statistical parameters of the protein-protein interaction network in combination with estimators of protein evolution. Conclusions.As functional genetic networks are becoming increasingly available, it will now be possible to evaluate functional genetic network constraint against variables describing complex phenotypes and environments, for better understanding of commonly observed deterministic patterns of evolution in non-model organisms. The hypothesis framework and methodological approach outlined herein may help to quantify the extrinsic versus intrinsic dimensions of evolutionary constraint, and result in a better understanding of how fast, effectively, or deterministically organisms adapt.