Modular Evolution of the Drosophila Metabolome

Abstract

Comparative phylogenetic studies offer a powerful approach to study the evolution of complex traits. While much effort has been devoted to the evolution of the genome and to organismal phenotypes, until now relatively little work has been done on the evolution of the metabolome, despite the fact that it is composed of the basic structural and functional building blocks of all organisms. Here we explore variation in metabolite levels across 50 million years of evolution in the genus Drosophila, employing a common garden design to measure the metabolome within and among 11 species of Drosophila. We find that both sex and age have dramatic and evolutionarily conserved effects on the metabolome. We also find substantial evidence that many metabolite pairs covary after phylogenetic correction, and that such metabolome coevolution is modular. Some of these modules are enriched for specific biochemical pathways and show different evolutionary trajectories, with some showing signs of stabilizing selection. Both observations suggest that functional relationships may ultimately cause such modularity. These coevolutionary patterns also differ between sexes and are affected by age. We explore the relevance of modular evolution to fitness by associating modules with lifespan variation measured in the same common garden. We find several modules associated with lifespan, particularly in the metabolome of older flies. Oxaloacetate levels in older females appear to coevolve with lifespan, and a lifespan-associated module in older females suggests that metabolic associations could underlie 50 million years of lifespan evolution.

Principles of metabolome conservation in animals

“…6A). We calculated metabolite-specific conservation scores using data on 92 non-lipid metabolites measured in whole adults of 11 Drosophila species under the same controlled environment 31 (Methods). Just as in mammals, MCS varies extensively across different metabolites, spanning over three orders of magnitude (Fig.…”

“…Absolute metabolite concentrations of 35 non-lipid metabolites were obtained from 32 . We used the metabolite concentrations measured in whole Drosophila melanogaster larvae samples, in order to best match the samples used in 31 . 24 of these 35 metabolites overlapped between the datasets.…”

“…This analysis included all specific metabolite -disease associations from MarkerDB, not just those involving the 11 broad disease condition categories. describing the evolutionary relationship between the species were obtained from 31 .…”

“…Conservation scores were computed as described above (see "Calculating the conservation scores of metabolites") 31 .…”

Combining Metabolomics and Experimental Evolution Reveals Key Mechanisms Underlying Longevity Differences in Laboratory Evolved Drosophila melanogaster Populations

“…Our conclusion that longevity differences in this system are tied to mitochondrial function and increased TCA cycle activity is supported by a number of metabolomic studies across different systems and species. For instance, results from work comparing metabolomic variation across eleven Drosophila species reports evidence that age and lifespan are associated with TCA cycle activity [82]. Another phylogenetic study comparing metabolomic and transcriptomic profiles across seventy-six wild yeast isolates also finds associations between replicative lifespan and TCA cycle activity and mitochondrial function [83].…”