ABSTRACT
Metabolic disorders commonly have a large heritable component, and have increased markedly over the past few generations. Genome-wide association studies of metabolic traits typically find a substantial unexplained fraction of the total heritability, suggesting an important role for the effects of spontaneous mutation. An alternative explanation, considered less likely, is that epigenetic effects contribute significantly to the heritable variation. Here we report a study designed to quantify the cumulative effects of spontaneous mutation on adenosine metabolism in the nematode Caenorhabditis elegans, including both the activity and concentration of two metabolic enzymes (ADA and ADK) and the standing pools of their associated metabolites. A previous study with the same set of C. elegans mutation accumulation (MA) lines found a large cumulative effect of mutation on adenosine concentration. The only prior study on the effects of mutation on metabolic enzyme activity, in Drosophila melanogaster, found that total enzyme activity presents a mutational target similar to that of morphological and life-history traits. However, those experiments were not designed to account for short-term heritable effects. We find that the means of some traits (6/17) change significantly over the course of ∼250 generations under MA conditions, consistent with previous findings, but that the short-term heritable variance for all but one trait (total soluble protein concentration) is of the same order of magnitude as the mutational variance. This result has important implications for the design and interpretation of MA studies, and suggests that the potential effects of epigenetic variation in human metabolic disease warrant additional scrutiny.