Principles of metabolome conservation in animals

Abstract

Metabolite concentrations shape cellular physiology and disease susceptibility, yet the general principles governing metabolome evolution are largely unknown. Here we introduce a measure of conservation of individual metabolite concentrations among related species. By analysing multispecies metabolome datasets in mammals and fruit flies, we show that conservation varies extensively across metabolites. Three major functional properties, metabolite abundance, essentiality and association with human diseases predict conservation, highlighting a striking parallel between the evolutionary forces driving metabolome and protein sequence conservation. Metabolic network simulations recapitulated these general patterns, and revealed that abundant metabolites are highly conserved due to their strong coupling to key metabolic fluxes in the network. This study uncovers simple rules governing metabolic evolution in animals and implies that most metabolome differences between species are permitted, rather than favored by selection. More broadly, our work paves the way towards using evolutionary information to discover biomarkers, as well as to detect pathogenic metabolome alterations in individual patients.

Widespread natural selection on metabolite levels in humans

“…If so, metabolites that are under stronger stabilizing selection in human populations are expected to be more evolutionarily conserved in their concentrations over macroevolutionary time scales. To test this hypothesis, we used a recent approach to infer a score that captures the extent of conservation of metabolite concentrations for individual metabolites based on cross-species comparisons 6 . We focused on a metabolomic dataset containing the relative concentrations of 249 metabolites in four major organs of 26 mammalian species, spanning an evolutionary period of ∼200 million 3 , and calculated an aggregated score of metabolite conservation across the four organs (see Methods).…”

“…Second, the agreement between alpha estimate and between-species conservation score suggests that the selective constraints preserving metabolite levels are at least partly shared between human and other mammalian species, including distantly related taxonomic groups. A recent study suggests that variation in evolutionary conservation across metabolites can be explained by a simple model where natural selection preserves flux through key metabolic reactions while permitting the accumulation of selectively neutral changes in enzyme activities 6 . Future works should test the extent to which this general model explains stabilizing selection on human metabolite levels.…”

“…However, not all metabolites are expected to be under equally strong stabilizing selection and there might be larger room for selectively neutral alterations for some metabolites than for others. Indeed, a recent multi-species comparison revealed wide differences in the extent of conservation of individual metabolite concentrations during evolution, likely driven by differing amounts of functional constraints across metabolites 6 . Furthermore, a remarkable acceleration of metabolome evolution has been reported in the human lineage compared to other primates, potentially indicating the action of directional selection on specific metabolites 7 .…”

The metabolic domestication syndrome of budding yeast

“…Recent research into the evolution of metabolite levels in mammals found similar results. It has been shown that evolutionary conservation of metabolite levels varies greatly among metabolites and can be explained by a neutral model ( 22 ).…”

“…In contrast, some variations in metabolite levels are likely non-functional (neutral), as evidenced by mutations that strongly impact metabolite levels without measurably altering fitness ( 20 , 21 ). Indeed, it has been recently proposed that much of the between-species variation in tissue metabolite levels in mammals are selectively neutral which are allowed, rather than favored by natural selection ( 22 ). However, the evolutionary driving forces of metabolite levels remain largely unresolved due to a shortage of comparative studies, especially in microbes.…”