title: Combined Use of Genome-Wide Association Data and Correlation Networks Unravels Key Regulators of Primary Metabolism in Arabidopsis thaliana.
abstract: Plant primary metabolism is a highly coordinated, central, and complex network of biochemical processes regulated at both the genetic and post-translational levels. The genetic basis of this network can be explored by analyzing the metabolic composition of genetically diverse genotypes in a given plant species. Here, we report an integrative strategy combining quantitative genetic mapping and metabolite‒transcript correlation networks to identify functional associations between genes and primary metabolites in Arabidopsis thaliana. Genome-wide association study (GWAS) was used to identify metabolic quantitative trait loci (mQTL). Correlation networks built using metabolite and transcript data derived from a previously published time-course stress study yielded metabolite‒transcript correlations identified by covariation. Finally, results obtained in this study were compared with mQTL previously described. We applied a statistical framework to test and compare the performance of different single methods (network approach and quantitative genetics methods, representing the two orthogonal approaches combined in our strategy) with that of the combined strategy. We show that the combined strategy has improved performance manifested by increased sensitivity and accuracy. This combined strategy allowed the identification of 92 candidate associations between structural genes and primary metabolites, which not only included previously well-characterized gene‒metabolite associations, but also revealed novel associations. Using loss-of-function mutants, we validated two of the novel associations with genes involved in tyrosine degradation and in β-alanine metabolism. In conclusion, we demonstrate that applying our integrative strategy to the largely untapped resource of metabolite-transcript associations can facilitate the discovery of novel metabolite-related genes. This integrative strategy is not limited to A. thaliana, but generally applicable to other plant species.
authors.affiliation: Max Planck Institute of Molecular Plant Physiology, Potsdam-Golm, Germany.
authors.forename: Si
authors.initials: S
authors.lastname: Wu
authors.affiliation: Max Planck Institute of Molecular Plant Physiology, Potsdam-Golm, Germany.
authors.forename: Saleh
authors.initials: S
authors.lastname: Alseekh
authors.affiliation: Max Planck Institute of Molecular Plant Physiology, Potsdam-Golm, Germany.|MetaSysX GmbH, Potsdam-Golm, Germany.
authors.forename: Álvaro
authors.initials: Á
authors.lastname: Cuadros-Inostroza
authors.affiliation: Max Planck Institute of Molecular Plant Physiology, Potsdam-Golm, Germany.
authors.forename: Corina M
authors.identifier: http://orcid.org/0000-0001-6809-0266
authors.initials: CM
authors.lastname: Fusari
authors.affiliation: Max Planck Institute of Molecular Plant Physiology, Potsdam-Golm, Germany.
authors.forename: Marek
authors.initials: M
authors.lastname: Mutwil
authors.affiliation: Laboratory of Genetics, Wageningen University, Wageningen, the Netherlands.
authors.forename: Rik
authors.identifier: http://orcid.org/0000-0002-8161-9811
authors.initials: R
authors.lastname: Kooke
authors.affiliation: Laboratory of Genetics, Wageningen University, Wageningen, the Netherlands.
authors.forename: Joost B
authors.identifier: http://orcid.org/0000-0001-8918-0711
authors.initials: JB
authors.lastname: Keurentjes
authors.affiliation: Max Planck Institute of Molecular Plant Physiology, Potsdam-Golm, Germany.
authors.forename: Alisdair R
authors.initials: AR
authors.lastname: Fernie
authors.affiliation: Max Planck Institute of Molecular Plant Physiology, Potsdam-Golm, Germany.
authors.forename: Lothar
authors.identifier: http://orcid.org/0000-0003-3297-825X
authors.initials: L
authors.lastname: Willmitzer
authors.affiliation: Max Planck Institute of Molecular Plant Physiology, Potsdam-Golm, Germany.|Department of Life Sciences, Ben Gurion University of the Negev, Beersheva, Israel.
authors.forename: Yariv
authors.initials: Y
authors.lastname: Brotman
mesh_terms: D000409:Alanine / Q000235:genetics / Q000378:metabolism; D017360:Arabidopsis / Q000235:genetics* / Q000378:metabolism; D029681:Arabidopsis Proteins / Q000235:genetics / Q000378:metabolism; D002874:Chromosome Mapping; D018506:Gene Expression Regulation, Plant; D014644:Genetic Variation; D018745:Genome, Plant; D055106:Genome-Wide Association Study; D005838:Genotype; D040641:Quantitative Trait Loci / Q000235:genetics*; D013223:Statistics as Topic; D014443:Tyrosine / Q000235:genetics / Q000378:metabolism
chemical_list: D029681:Arabidopsis Proteins; D014443:Tyrosine; D000409:Alanine