Considerations when choosing a genetic model organism for metabolomics studies

Abstract

Model organisms are important in many areas of chemical biology. In metabolomics, model organisms can provide excellent samples for methods development as well as the foundation of comparative phylometabolomics, which will become possible as metabolomics applications expand. Comparative studies of conserved and unique metabolic pathways will help in the annotation of metabolites as well as provide important new targets of investigation in biology and biomedicine. However, most chemical biologists are not familiar with genetics, which needs to be considered when choosing a model organism. In this review we summarize the strengths and weaknesses of several genetic systems, including natural isolates, recombinant inbred lines, and genetic mutations. We also discuss methods to detect targets of selection on the metabolome.

Figure 1. Sources of interesting biological variation that contribute to observable phenotypes

The components of a system in a population of organisms include: genetic variation (hard coded genetic information in DNA), the epigenome (controls on how and when the genetic information is expressed), the transcriptome (all of the RNA gene transcripts), the proteome (the complete set of proteins translated and subsequently modified from the RNA transcripts), the metabolome (all the small molecule chemical compounds from both endogenous and exogenous sources). To understand complex traits, including disease, ultimately we have to understand each “omics” level, how it evolves, and the mechanisms by which it can be perturbed. Phenotypic variation derives not only from genetic variation but also from the environment that can introduce both predictable and random perturbation (lightning bolts) of the physiological system. Metabolic homeostasis is achieved through interactions between different physiological or “omics” levels within an organism, including regulatory feedback (curved arrows) and the fitness effects on the evolutionary genetics of the species. Each physiological level is likely to have a distinct reaction to environmental perturbation thus have to be understood as part of a larger system to predict the phenotypic consequence.

Figure 2. The genetic basis for variation in the metabolome can be identified by several strategies

The metabolome is symbolized here by small colored nodes for metabolites with edges between the nodes indicating a gene function that links two metabolites (e.g an enzyme). The color of the larger circles containing the metabolome represents the phenotype of the organism. A. A natural population exhibits inter-individual variation in the structure of their metabolomes and resulting phenotypes due to a combination genotype (α, β, or γ) and environmental (1, 2, or 3) effects. B. The relative contribution of genotype and environment to metabolome variation can be identified by systematically testing the distinct genotypes (α, β, and γ) across each of the three environments. This can be a powerful way to map the genes contributing to metabolome variation in natural isolates and recombinant inbred lines (RILs). C. Systematic mutation of the genes (red X) contributing to the metabolome can identify which are most critical to maintaining the organism's phenotype when compared to the wildtype (α) genetic control (e.g. orange vs blue phenotype). D. Artificial selection exposes a genetically variable population to a selective force such as a novel environment that selects for a phenotype and underlying metabolome controlled by particular genes. By analyzing how the metabolome network adapts one can identify especially important components (e.g. new connection between the blue and orange metabolites). E. Mutation accumulation (MA) experiments allow a wildtype progenitor genotype (α) to progressively acquire mutations that are largely deleterious. The comparison between the wildtype and MA lines allows for the identification of especially critical genetic controls and the overall robustness of the metabolome (e.g. blue vs pink phenotypes).