Natural genetic variation in<i>C. elegans</i>identified genomic loci controlling metabolite levels

Gao, Arwen W.; Sterken, M.G.; Bos, Jelmi uit de; Creij, Jelle van; Kamble, Rashmi; Snoek, L. Basten; Kammenga, J.E.; Houtkooper, Riekelt H.

doi:10.1101/gr.232322.117

Cited by 31 publications

(28 citation statements)

References 56 publications

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“…Furthermore, it shows how ILs can be used to narrow-down these eQTL hotspots (Snoek et al, 2012), using correlation analysis previously used to link trans-bands to genes and biological processes (Andersen et al, 2014;Sterken et al, 2017). These findings show on a large scale that QTL mapped using a single marker model in a moderately sized RIL population are reliably replicable in a population with a different genetic structure, which confirms findings for single traits reported in C. elegans and beyond [for example, see (Snoek et al, 2012;Andersen et al, 2014;Gao et al, 2018)].…”

Section: Most Eqtl Mapped In Rils Are Replicable In Ilssupporting

confidence: 77%

Dissecting the eQTL Micro-Architecture in Caenorhabditis elegans

et al. 2020

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The study of expression quantitative trait loci (eQTL) using natural variation in inbred populations has yielded detailed information about the transcriptional regulation of complex traits. Studies on eQTL using recombinant inbred lines (RILs) led to insights on cis and trans regulatory loci of transcript abundance. However, determining the underlying causal polymorphic genes or variants is difficult, but ultimately essential for the understanding of regulatory networks of complex traits. This requires insight into whether associated loci are single eQTL or a combination of closely linked eQTL, and how this QTL micro-architecture depends on the environment. We addressed these questions by testing for independent replication of previously mapped eQTL in Caenorhabditis elegans using new data from introgression lines (ILs). Both populations indicate that the overall heritability of gene expression, number, and position of eQTL differed among environments. Across environments we were able to replicate 70% of the cis-and 40% of the trans-eQTL using the ILs. Testing eight different simulation models, we suggest that additive effects explain up to 60-93% of RIL/IL heritability for all three environments. Closely linked eQTL explained up to 40% of RIL/IL heritability in the control environment whereas only 7% in the heat-stress and recovery environments. In conclusion, we show that reproducibility of eQTL was higher for cis vs. trans eQTL and that the environment affects the eQTL micro-architecture.

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Section: Most Eqtl Mapped In Rils Are Replicable In Ilssupporting

confidence: 77%

Dissecting the eQTL Micro-Architecture in Caenorhabditis elegans

et al. 2020

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“…C. elegans is a self-fertilizing hermaphrodite and, therefore, different wild strains can be easily maintained as fully isogenic strains. These different strains have been used to identify quantitative trait loci (QTL) that contribute to a variety of phenotypes, including anthelmintic and cancer chemotherapeutic resistance, and in several cases the precise genotypic variation that is causal to phenotypic variation has been determined [24][25][26][27][28][29][30]. Genomic information about the different strains is organized in the C. elegans Natural Diversity Resource (CeNDR), along with different tools for genome-wide association (GWA) mappings [31].…”

Section: Introductionmentioning

confidence: 99%

Natural variation in a glucuronosyltransferase modulates propionate sensitivity in a C. elegans propionic acidemia model

Zdraljevic

Tanny

et al. 2020

PLoS Genet

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Mutations in human metabolic genes can lead to rare diseases known as inborn errors of human metabolism. For instance, patients with loss-of-function mutations in either subunit of propionyl-CoA carboxylase suffer from propionic acidemia because they cannot catabolize propionate, leading to its harmful accumulation. Both the penetrance and expressivity of metabolic disorders can be modulated by genetic background. However, modifiers of these diseases are difficult to identify because of the lack of statistical power for rare diseases in human genetics. Here, we use a model of propionic acidemia in the nematode Caenorhabditis elegans to identify genetic modifiers of propionate sensitivity. Using genome-wide association (GWA) mapping across wild strains, we identify several genomic regions correlated with reduced propionate sensitivity. We find that natural variation in the putative glucuronosyltransferase GLCT-3, a homolog of human B3GAT, partly explains differences in propionate sensitivity in one of these genomic intervals. We demonstrate that loss-of-function alleles in glct-3 render the animals less sensitive to propionate. Additionally, we find that C. elegans has an expansion of the glct gene family, suggesting that the number of members of this family could influence sensitivity to excess propionate. Our findings demonstrate that natural variation in genes that are not directly associated with propionate breakdown can modulate propionate sensitivity. Our study provides a framework for using C. elegans to characterize the contributions of genetic background in models of human inborn errors in metabolism.

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“…Yet, studying genetically variable C. elegans strains will provide a broader view on the genetic architecture of host-pathogen interactions (Table 1). Over the past two decades, C. elegans has been established as a platform for studying the genetic architecture of complex traits using quantitative genetic analyses based on genetic variation [11,12]. A range of complex phenotypes have been mapped to loci and genetic variants using genetic linkage studies or genome-wide association approaches [13].…”

Section: Genetic Variation In Caenorhabditis Elegans As the Basis To mentioning

confidence: 99%

Genetic Variation in Caenorhabditis elegans Responses to Pathogenic Microbiota

Huang

Kammenga

2020

Microorganisms

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The bacterivorous nematode Caenorhabditis elegans is an important model species for understanding genetic variation of complex traits. So far, most studies involve axenic laboratory settings using Escherichia coli as the sole bacterial species. Over the past decade, however, investigations into the genetic variation of responses to pathogenic microbiota have increasingly received attention. Quantitative genetic analyses have revealed detailed insight into loci, genetic variants, and pathways in C. elegans underlying interactions with bacteria, microsporidia, and viruses. As various quantitative genetic platforms and resources like C. elegans Natural Diversity Resource (CeNDR) and Worm Quantitative Trait Loci (WormQTL) have been developed, we anticipate that expanding C. elegans research along the lines of genetic variation will be a treasure trove for opening up new insights into genetic pathways and gene functionality of microbiota interactions.

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Natural genetic variation inC. elegansidentified genomic loci controlling metabolite levels

Cited by 31 publications

References 56 publications

Dissecting the eQTL Micro-Architecture in Caenorhabditis elegans

Dissecting the eQTL Micro-Architecture in Caenorhabditis elegans

Natural variation in a glucuronosyltransferase modulates propionate sensitivity in a C. elegans propionic acidemia model

Genetic Variation in Caenorhabditis elegans Responses to Pathogenic Microbiota

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