Natural genetic variation in identified genomic loci controlling metabolite levels

Arwen W Gao, Mark G Sterken, Jelmi Uit de Bos, Jelle van Creij, Rashmi Kamble, Basten L Snoek, Jan E Kammenga, Riekelt H Houtkooper

Research output: Contribution to journal/periodicalArticleScientificpeer-review

Abstract

Metabolic homeostasis is sustained by complex biological networks that respond to nutrient availability. Genetic and environmental factors may disrupt this equilibrium, leading to metabolic disorders, including obesity and type 2 diabetes. To identify the genetic factors controlling metabolism, we performed quantitative genetic analysis using a population of 199 recombinant inbred lines (RILs) in the nematode Caenorhabditis elegans We focused on the genomic regions that control metabolite levels by measuring fatty acid (FA) and amino acid (AA) composition in the RILs using targeted metabolomics. The genetically diverse RILs showed a large variation in their FA and AA levels with a heritability ranging from 32% to 82%. We detected strongly co-correlated metabolite clusters and 36 significant metabolite quantitative trait loci (mQTL). We focused on mQTL displaying highly significant linkage and heritability, including an mQTL for the FA C14:1 on Chromosome I, and another mQTL for the FA C18:2 on Chromosome IV. Using introgression lines (ILs), we were able to narrow down both mQTL to a 1.4-Mbp and a 3.6-Mbp region, respectively. RNAi-based screening focusing on the Chromosome I mQTL identified several candidate genes for the C14:1 mQTL, including lagr-1, Y87G2A.2, nhr-265, nhr-276, and nhr-81 Overall, this systems approach provides us with a powerful platform to study the genetic basis of C. elegans metabolism. Furthermore, it allows us to investigate interventions such as nutrients and stresses that maintain or disturb the regulatory network controlling metabolic homeostasis, and identify gene-by-environment interactions.

Original languageEnglish
Pages (from-to)1296-1308
Number of pages13
JournalGenome Research
Volume28
Issue number9
DOIs
Publication statusPublished - Sep 2018
Externally publishedYes

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Gao, A. W., Sterken, M. G., Uit de Bos, J., van Creij, J., Kamble, R., Snoek, B. L., Kammenga, J. E., & Houtkooper, R. H. (2018). Natural genetic variation in identified genomic loci controlling metabolite levels. Genome Research, 28(9), 1296-1308. https://doi.org/10.1101/gr.232322.117