Natural genetic variation in C. elegans 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 journalArticleAcademicpeer-review

5 Citations (Scopus)

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 andAAlevels with a heritability ranging from 32% to 82%. We detected strongly co-correlated metabolite clusters and 36 significant metabolite QTL (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
JournalGenome Research
Volume28
Issue number8
DOIs
Publication statusPublished - 14 Aug 2018

Fingerprint

Fatty Acids
Caenorhabditis elegans
Homeostasis
Food
Gene-Environment Interaction
Metabolomics
Chromosomes, Human, Pair 2
Chromosomes, Human, Pair 1
RNA Interference
Metabolic Networks and Pathways
Type 2 Diabetes Mellitus
Obesity
Chromosomes
Amino Acids
Population
Genes

Cite this

Gao, Arwen W. ; Sterken, Mark G. ; Uit De Bos, Jelmi ; van Creij, Jelle ; Kamble, Rashmi ; Snoek, Basten L. ; Kammenga, Jan E. ; Houtkooper, Riekelt H. / Natural genetic variation in C. elegans identified genomic loci controlling metabolite levels. In: Genome Research. 2018 ; Vol. 28, No. 8. pp. 1296-1308.
@article{c418d5291f104d8e8f0fabbb766f11f7,
title = "Natural genetic variation in C. elegans identified genomic loci controlling metabolite levels",
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 andAAlevels with a heritability ranging from 32{\%} to 82{\%}. We detected strongly co-correlated metabolite clusters and 36 significant metabolite QTL (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 systemsapproach 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.",
author = "Gao, {Arwen W.} and Sterken, {Mark G.} and {Uit De Bos}, Jelmi and {van Creij}, Jelle and Rashmi Kamble and Snoek, {Basten L.} and Kammenga, {Jan E.} and Houtkooper, {Riekelt H.}",
year = "2018",
month = "8",
day = "14",
doi = "10.1101/gr.232322.117",
language = "English",
volume = "28",
pages = "1296--1308",
journal = "Genome Research",
issn = "1088-9051",
publisher = "Cold Spring Harbor Laboratory Press",
number = "8",

}

Natural genetic variation in C. elegans identified genomic loci controlling metabolite levels. / Gao, Arwen W.; Sterken, Mark G.; Uit De Bos, Jelmi; van Creij, Jelle; Kamble, Rashmi; Snoek, Basten L.; Kammenga, Jan E.; Houtkooper, Riekelt H.

In: Genome Research, Vol. 28, No. 8, 14.08.2018, p. 1296-1308.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Natural genetic variation in C. elegans identified genomic loci controlling metabolite levels

AU - Gao, Arwen W.

AU - Sterken, Mark G.

AU - Uit De Bos, Jelmi

AU - van Creij, Jelle

AU - Kamble, Rashmi

AU - Snoek, Basten L.

AU - Kammenga, Jan E.

AU - Houtkooper, Riekelt H.

PY - 2018/8/14

Y1 - 2018/8/14

N2 - 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 andAAlevels with a heritability ranging from 32% to 82%. We detected strongly co-correlated metabolite clusters and 36 significant metabolite QTL (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 systemsapproach 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.

AB - 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 andAAlevels with a heritability ranging from 32% to 82%. We detected strongly co-correlated metabolite clusters and 36 significant metabolite QTL (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 systemsapproach 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.

U2 - 10.1101/gr.232322.117

DO - 10.1101/gr.232322.117

M3 - Article

VL - 28

SP - 1296

EP - 1308

JO - Genome Research

JF - Genome Research

SN - 1088-9051

IS - 8

ER -