Trade-Offs Predicted by Metabolic Network Structure Give Rise to Evolutionary Specialization and Phenotypic Diversification

Abstract

Mitigating trade-offs between different resource-utilization functions is key to an organism’s ecological and evolutionary success. These trade-offs often reflect metabolic constraints with a complex molecular underpinning; therefore, their consequences for evolutionary processes have remained elusive. Here, we investigate how metabolic architecture induces resource utilization constraints and how these constraints, in turn, elicit evolutionary specialization and diversification. Guided by the metabolic network structure of the bacterium Lactococcus cremoris, we selected two carbon sources (fructose and galactose) with predicted co-utilization constraints. By evolving L. cremoris on either fructose, galactose or a mix of both sugars, we imposed selection favoring divergent metabolic specializations or co-utilization of both resources, respectively. Phenotypic characterization revealed the evolution of either fructose or galactose specialists in the single-sugar treatments. In the mixed sugar regime, we observed adaptive diversification: both specialists coexisted, and no generalist evolved. Divergence from the ancestral phenotype occurred at key pathway junctions in the central carbon metabolism. Fructose specialists evolved mutations in the fbp and pfk genes that appear to balance anabolic and catabolic carbon fluxes. Galactose specialists evolved increased expression of pgmA (the primary metabolic bottleneck of galactose metabolism) and silencing of ptnABCD (the main glucose transporter) and ldh (regulator/enzyme of downstream carbon metabolism). Overall, our study shows how metabolic network architecture and historical contingency serve to predict targets of selection and inform the functional interpretation of evolved mutations. The elucidation of the relationship between molecular constraints and phenotypic trade-offs contributes to an integrative understanding of evolutionary specialization and diversification.

Models and molecular mechanisms for trade‐offs in the context of metabolism

“…Second, while the concept of identification of trade-offs from omics data has caught considerable attention (Shoval et al, 2012), the problem of predicting which trade-offs arise under specific conditions remains poorly understood. A recent study has made progress in this direction by making use of the knowledge of metabolic network structure to predict which functions interact antagonistically or agonistically to facilitate adaptation of Lactococcus cremoris to a specific carbon source (Ekkers et al, 2022). Specifically, the study predicted and tested the hypothesis that adaptation to galactose and fructose, as carbon sources, will target pathway branch points and reactions in glycolysis-reactions that need adjustment in comparison to the pre-adapted growth on glucose.…”

“…In addition, there are gaps in our ability to predict the impact of different environments in the attenuation or strengthening of trade‐offs. It has already been recognized that models of trade‐offs that rely on the integration of cellular networks can provide the means to address these challenges (Ekkers et al, 2022; Mauro & Ghalambor, 2020; Stearns, 1989). To this end, metabolic modelling studies have already begun to address the problems of identifying, and explaining, metabolic trade‐offs (Pfeiffer et al, 2001; Schuetz et al, 2012).…”

Endo metabolomic profiling of flor and wine yeasts reveals a positive correlation between intracellular metabolite load and the specific glycolytic flux during wine fermentation

“…Resource-utilization strategies are intimately linked to metabolic trade-off and are subjected to natural selection. For example, individuals of the same species may take different paths of metabolic adaptation in a changing environment, as recently demonstrated (Ekkers et al, 2022).…”