Natural genetic variation in C. elegans identified genomic loci controlling metabolite levels.
Natural genetic variation in C. elegans identified genomic loci controlling metabolite levels.
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DOI：
10.1101/gr.232322.117
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发表时间：
2018-09
期刊：
影响因子：
7
通讯作者：
Houtkooper RH
中科院分区：
文献类型：
--
作者：
Gao AW;Sterken MG;Uit de Bos J;van Creij J;Kamble R;Snoek BL;Kammenga JE;Houtkooper RH
代谢稳态是由复杂的生物网络来维持的，这些网络对营养的可用性做出反应。遗传和环境因素可能会破坏这种平衡，导致代谢紊乱，包括肥胖和2型糖尿病。为了确定控制代谢的遗传因素，我们使用199个重组自交系（RILs）的线虫秀丽隐杆线虫的人口进行定量遗传分析。我们专注于基因组区域，控制代谢物水平，通过测量脂肪酸（FA）和氨基酸（AA）组成的RILs使用靶向代谢组学。遗传多样的RILs表现出很大的变化，其FA和AA水平的遗传力范围从32%到82%。我们检测到强烈的共相关的代谢物集群和36个重要的代谢物数量性状位点（mQTL）。我们集中在mQTL显示高度显着的连锁和遗传力，包括一个mQTL的FA C14：1染色体上，和另一个mQTL的FA C18：2染色体上的IV。使用渐渗系（IL），我们能够缩小两个mQTL的1.4-Mbp和3.6-Mbp的区域，分别。基于RNAi的筛选集中在染色体I mQTL上，鉴定了C14：1 mQTL的几个候选基因，包括lagr-1、Y87G2A.2、nhr-265、nhr-276和nhr-81。总体而言，这种系统方法为我们提供了一个强大的平台，研究遗传基础的C。elegans代谢此外，它使我们能够调查干预措施，如营养素和压力，维持或干扰控制代谢稳态的调节网络，并确定基因与环境的相互作用。
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.
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影响因子：
30.8
作者：
Andersen, Erik C.;Gerke, Justin P.;Shapiro, Joshua A.;Crissman, Jonathan R.;Ghosh, Rajarshi;Bloom, Joshua S.;Felix, Marie-Anne;Kruglyak, Leonid
通讯作者：
Kruglyak, Leonid
影响因子：
4.5
作者：
Kammenga JE;Doroszuk A;Riksen JA;Hazendonk E;Spiridon L;Petrescu AJ;Tijsterman M;Plasterk RH;Bakker J
通讯作者：
Bakker J
影响因子：
11.1
作者：
Gao, Arwen W.;Canto, Carles;Houtkooper, Riekelt H.
通讯作者：
Houtkooper, Riekelt H.
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y
影响因子：
64.5
作者：
Andreux, Penelope A.;Williams, Evan G.;Auwerx, Johan
通讯作者：
Auwerx, Johan