The Complex Genetic Architecture of the Metabolome

The Complex Genetic Architecture of the Metabolome

http://www.plosgenetics.org/article/info%3Adoi%2F10.1371%2Fjournal.pgen.1001198

Understanding how genetic variation can control phenotypic variation is a fundamental goal of modern biology. We combined genome-wide association mapping with metabolomics in the plant Arabidopsis thaliana to explore how species-wide genetic variation controls metabolism. We identified numerous naturally-variable genes that may influence plant metabolism, often clustering in “hotspots.” These hotspots were proximal to selective sweeps, regions of the genome showing decreased diversity possibly from a strong selective advantage of specific variants within the region. This suggests that metabolism may be connected to the selective advantage. Interestingly, metabolite variation in wild Arabidopsis is highly constrained despite the significant genetic variation, thus providing the plant un-sampled metabolic space if the environment shifts. The observed structuring of genetic and metabolic variation suggests individual convergence upon similar phenotypes via different genotypes, possibly intra-specific parallel evolution. This phenotypic convergence couples with a pattern of genotype—phenotype association consistent with metabolite variation largely controlled by numerous small effect genetic variants. This supports the supposition that large magnitude variation is likely unstable in a complex and interconnected metabolism. If this pattern proves generally applicable to other species, it could present a significant hurdle to identifying genes controlling metabolic trait variation via genome-wide association studies.