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Mol Biol Evol. 2017 Dec 1;34(12):3111-3122. doi: 10.1093/molbev/msx234.

A Highly Specific Genome-Wide Association Study Integrated with Transcriptome Data Reveals the Contribution of Copy Number Variations to Specialized Metabolites in Arabidopsis thaliana Accessions.

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Frontier Research Academy for Young Researchers, Kyushu Institute of Technology, Fukuoka, Japan.
Center for Sustainable Resource Science, RIKEN, Kanagawa, Japan.
Department of Bioinformatic Engineering, Graduate School of Information Science and Technology, Osaka University, Osaka, Japan.
Center for Bioscience Research and Education, Utsunomiya University, Utsunomiya, Japan.
Department of Drug Discovery Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Center for Integrative Medical Sciences, RIKEN, Kanagawa, Japan.
Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan.


Lineage-specific gene duplications contribute to a large variation in specialized metabolites among different plant species. There is also considerable variability in the specialized metabolites within a single plant species. However, it is unclear whether copy number variations (CNVs) derived from gene duplication events contribute to the diversity of specialized metabolites within species. We identified metabolome quantitative trait genes (mQTGs) associated with quantitative metabolite variations and examined the relationship between mQTGs and CNVs. We obtained 1,335 specialized metabolite signals from 53 worldwide A. thaliana accessions using liquid chromatography-quadrupole time-of-flight mass spectrometry. In this study, genes associated with specialized metabolites were inferred by either a generally authorized genome-wide association study (GWAS) approach or a novel analysis of the association between gene expression and metabolite accumulation. Genes qualified by both analyses are defined to be mQTGs. The integrated method enabled us to detect mQTGs with a low false positive rate (=5.71 × 10-4). We also identified 5,654 genes associated with 1,335 specialized metabolites. Of these genes, 4.4% were affected by CNVs, which was more than expected (χ2 test: P < 0.01). This result suggests that CNVs contribute to variations in specialized metabolites within a species. To assess the contribution of CNVs to adaptive evolution in A. thaliana, we examined the selective sweeps around the mQTGs. We observed that the mQTGs with CNVs tended to undergo selective sweeps. These observations imply that variations in specialized metabolites caused by CNVs contribute to the adaptive evolution of A. thaliana.


Arabidopsis thaliana; adaptive evolution; copy number variation; genome-wide association study; selective sweep; specialized metabolite

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