The effect of developmental variation on expression QTLs in a multi parental Caenorhabditis elegans population.

Regulation of gene expression plays a crucial role in developmental processes and adaptation to changing environments. expression quantitative trait locus (eQTL) mapping is a technique used to study the genetic regulation of gene expression using the transcriptomes of recombinant inbred lines (RILs). Typically, the age of the inbred lines at the time of RNA sampling is carefully controlled. This is necessary because the developmental process causes changes in gene expression, complicating the interpretation of eQTL mapping experiments. However, due to genetics and variation in ambient micro-environments, organisms can differ in their "developmental age," even if they are of the same chronological age. As a result, eQTL patterns are affected by developmental variation in gene expression. The model organism Caenorhabditis elegans is particularly suited for studying the effect of developmental variation on eQTL mapping patterns. In a span of days, C. elegans transitions from embryo through 4 larval stages to adult while undergoing massive changes to its transcriptome. Here, we use C. elegans to investigate the effect of developmental age variation on eQTL patterns and present a normalization procedure. We used dynamical eQTL mapping, which includes the developmental age as a cofactor, to separate the variation in development from genotypic variation and explain variation in gene expression levels. We compare classical single marker eQTL mapping and dynamical eQTL mapping using RNA-seq data of ∼200 multi-parental RILs of C. elegans. The results show that (1) many eQTLs are caused by developmental variation, (2) most trans-bands are developmental QTLs, and (3) dynamical eQTL mapping detects additional eQTLs not found with classical eQTL mapping. We recommend that correction for variation in developmental age should be strongly considered in eQTL mapping studies given the large impact of processes like development on the transcriptome.

Natural allelic variation modifies acute ethanol response phenotypes in wild strains of C. elegans.

BACKGROUND: Genetic variation contributes to the likelihood that an individual will develop an alcohol use disorder (AUD). Traditional laboratory studies in animal models have elucidated the molecular pharmacology of ethanol, but laboratory-derived genetic manipulations rarely model the naturally occurring genetic variation observed in wild populations. Rather, these manipulations are biased toward identifying genes of central importance in the phenotypes. Because changes in such genes can confer selective disadvantages, they are not ideal candidates for carrying AUD risk alleles in humans. We sought to exploit Caenorhabditis elegans to identify allelic variation existing in the wild that modulates ethanol response behaviors. METHODS: We tested the acute ethanol responses of four strains recently isolated from the wild (JU1511, JU1926, JU1931, and JU1941) and 41 multiparental recombinant inbred lines (mpRILs) derived from them. We assessed locomotion at 10, 30, and 50 min on low and high ethanol concentrations. We performed principal component analyses (PCA) on the different phenotypes, tested for transgressive behavior, calculated heritability, and determined the correlations between behavioral responses. RESULTS: We observed a range of responses to ethanol across the strains. We detected a low-concentration locomotor activation effect in some of the mpRILs not seen in the laboratory wild-type strain. PCA showed different ethanol response behaviors to be independent. We observed transgressive behavior for many of the measured phenotypes and found that multiple behaviors were uncorrelated. The average broad-sense heritability for all phenotypes was 23.2%. CONCLUSIONS: Genetic variation significantly affects multiple acute ethanol response behaviors, many of which are independent of one another. This suggests that the genetic variation captured by these strains likely affects multiple biological mechanisms through which ethanol acts. Further study of these strains may allow these distinct mechanisms to be identified.

Cryptic genetic variation of expression quantitative trait locus architecture revealed by genetic perturbation in Caenorhabditis elegans.

Genetic perturbation in different genetic backgrounds can cause a range of phenotypes within a species. These phenotypic differences can be the result of the interaction between the genetic background and the perturbation. Previously, we reported that perturbation of gld-1, an important player in the developmental control of Caenorhabditis elegans, released cryptic genetic variation (CGV) affecting fitness in different genetic backgrounds. Here, we investigated the change in transcriptional architecture. We found 414 genes with a cis-expression quantitative trait locus (eQTL) and 991 genes with a trans-eQTL that were specifically found in the gld-1 RNAi treatment. In total, we detected 16 eQTL hotspots, of which 7 were only found in the gld-1 RNAi treatment. Enrichment analysis of those 7 hotspots showed that the regulated genes were associated with neurons and the pharynx. Furthermore, we found evidence of accelerated transcriptional aging in the gld-1 RNAi-treated nematodes. Overall, our results illustrate that studying CGV leads to the discovery of hidden polymorphic regulators.

The genetic architecture underlying body-size traits plasticity over different temperatures and developmental stages in Caenorhabditis elegans.

Most ectotherms obey the temperature-size rule, meaning they grow larger in a colder environment. This raises the question of how the interplay between genes and temperature affects the body size of ectotherms. Despite the growing body of literature on the physiological life-history and molecular genetic mechanism underlying the temperature-size rule, the overall genetic architecture orchestrating this complex phenotype is not yet fully understood. One approach to identify genetic regulators of complex phenotypes is quantitative trait locus (QTL) mapping. Here, we explore the genetic architecture of body-size phenotypes, and plasticity of body-size phenotypes at different temperatures using Caenorhabditis elegans as a model ectotherm. We used 40 recombinant inbred lines (RILs) derived from N2 and CB4856, which were reared at four different temperatures (16, 20, 24, and 26 °C) and measured at two developmental stages (L4 and adult). The animals were measured for body length, width at vulva, body volume, length/width ratio, and seven other body-size traits. The genetically diverse RILs varied in their body-size phenotypes with heritabilities ranging from 0.0 to 0.99. We detected 18 QTL underlying the body-size traits across all treatment combinations, with the majority clustering on Chromosome X. We hypothesize that the Chromosome X QTL could result from a known pleiotropic regulator-npr-1-known to affect the body size of C. elegans through behavioral changes. We also found five plasticity QTL of body-size traits where three colocalized with body-size QTL. In conclusion, our findings shed more light on multiple loci affecting body-size plasticity and the possibility of co-regulation of traits and traits plasticity by the same loci under different environments.

Differential expression of genes in C. elegans reveals transcriptional responses to indirect-acting xenobiotic compounds and insensitivity to 2,3,7,8-tetrachlorodibenzodioxin.

Caenorhabditis elegans is a well-established model organism for toxicity testing of chemical substances. We recently demonstrated its potential for bioanalysis of the toxic potency of chemical contaminants in water. While many detoxification genes are homologues to those in mammalians, C. elegans is reported to be deficient in cytochrome CYP1-like P450 metabolism and that its aryl hydrocarbon receptor (AhR) homolog encoded by ahr-1 purportedly does not interact with dioxins or any other known xenobiotic ligand. This suggests that C. elegans is insensitive for compounds that require bioactivation (indirectly acting compounds) and for dioxins or dioxin-like compounds. This study analysed genome-wide gene expression of the nematode in response to 30 µM of aflatoxin B1 (AFB1), benzo(a)pyrene (B(a)P), Aroclor 1254 (PCB1254), and 10 µM of 2,3,7,8-tetrachlorodibenzodioxin (TCDD). After 24 h of exposure in the early L4 larval stage, microarray analysis revealed 182, 86, and 321 differentially expressed genes in the nematodes treated with 30 µM of AFB1, B(a)P, and PCB1254, respectively. Among these genes, many encode xenobiotic-metabolizing enzymes, and their transcription levels were among the highest-ranked fold-changed genes. Interestingly, only one gene (F59B1.8) was upregulated in the nematodes exposed to 10 µM TCDD. Genes related to metabolic processes and catalytic activity were the most induced by exposure to 30 µM of AFB1, B(a)P, and PCB1254. Despite the genotoxic nature of AFB1 and B(a)P, no differential expression was found in the genes encoding DNA repair and cell cycle checkpoint proteins. Analysis of concentration-response curves was performed to determine the Lowest Observed Transcriptomic Effect Levels (LOTEL) of AFB1, B(a)P, and PCB1254. The obtained LOTEL values showed that gene expression changes in C. elegans are more sensitive to toxicants than reproductive effects. Overall, transcriptional responses of metabolic enzymes suggest that the nematode does metabolize AFB1, B(a)P, and PCB1254. Our findings also support the assumption that the transcription factor AhR homolog in C. elegans does not bind typical xenobiotic ligands, rendering the nematode transcriptionally insensitive to TCDD effects.

On the role of dauer in the adaptation of nematodes to a parasitic lifestyle.

Nematodes are presumably the most abundant Metazoa on Earth, and can even be found in some of the most hostile environments of our planet. Various types of hypobiosis evolved to adapt their life cycles to such harsh environmental conditions. The five most distal major clades of the phylum Nematoda (Clades 8-12), formerly referred to as the Secernentea, contain many economically relevant parasitic nematodes. In this group, a special type of hypobiosis, dauer, has evolved. The dauer signalling pathway, which culminates in the biosynthesis of dafachronic acid (DA), is intensively studied in the free-living nematode Caenorhabditis elegans, and it has been hypothesized that the dauer stage may have been a prerequisite for the evolution of a wide range of parasitic lifestyles among other nematode species. Biosynthesis of DA is not specific for hypobiosis, but if it results in exit of the hypobiotic state, it is one of the main criteria to define certain behaviour as dauer. Within Clades 9 and 10, the involvement of DA has been validated experimentally, and dauer is therefore generally accepted to occur in those clades. However, for other clades, such as Clade 12, this has hardly been explored. In this review, we provide clarity on the nomenclature associated with hypobiosis and dauer across different nematological subfields. We discuss evidence for dauer-like stages in Clades 8 to 12 and support this with a meta-analysis of available genomic data. Furthermore, we discuss indications for a simplified dauer signalling pathway in parasitic nematodes. Finally, we zoom in on the host cues that induce exit from the hypobiotic stage and introduce two hypotheses on how these signals might feed into the dauer signalling pathway for plant-parasitic nematodes. With this work, we contribute to the deeper understanding of the molecular mechanisms underlying hypobiosis in parasitic nematodes. Based on this, novel strategies for the control of parasitic nematodes can be developed.

Development of a transcription-based bioanalytical tool to quantify the toxic potencies of hydrophilic compounds in water using the nematode Caenorhabditis elegans.

Low concentrations of environmental contaminants can be difficult to detect with current analytical tools, yet they may pose a risk to human and environmental health. The development of bioanalytical tools can help to quantify toxic potencies of biologically active compounds even of hydrophilic contaminants that are hard to extract from water samples. In this study, we exposed the model organism Caenorhabditis elegans synchronized in larval stage L4 to hydrophilic compounds via the water phase and analyzed the effect on gene transcription abundance. The nematodes were exposed to three direct-acting genotoxicants (1 mM and 5 mM): N-ethyl-N-nitrosourea (ENU), formaldehyde (HCHO), and methyl methanesulfonate (MMS). Genome-wide gene expression analysis using microarrays revealed significantly altered transcription levels of 495 genes for HCHO, 285 genes for ENU, and 569 genes for MMS in a concentration-dependent manner. A relatively high number of differentially expressed genes was downregulated, suggesting a general stress in nematodes treated with toxicants. Gene ontology and Kyoto encyclopedia of genes and genomes analysis demonstrated that the upregulated genes were primarily associated with metabolism, xenobiotic detoxification, proteotoxic stress, and innate immune response. Interestingly, genes downregulated by MMS were linked to the inhibition of neurotransmission, and this is in accordance with the observed decreased locomotion in MMS-exposed nematodes. Unexpectedly, the expression level of DNA damage response genes such as cell-cycle checkpoints or DNA-repair proteins were not altered. Overall, the current study shows that gene expression profiling of nematodes can be used to identify the potential mechanisms underlying the toxicity of chemical compounds. C. elegans is a promising test organism to further develop into a bioanalytical tool for quantification of the toxic potency of a wide array of hydrophilic contaminants.

The genetics of gene expression in a Caenorhabditis elegans multiparental recombinant inbred line population.

Studying genetic variation of gene expression provides a powerful way to unravel the molecular components underlying complex traits. Expression quantitative trait locus (eQTL) studies have been performed in several different model species, yet most of these linkage studies have been based on the genetic segregation of two parental alleles. Recently, we developed a multiparental segregating population of 200 recombinant inbred lines (mpRILs) derived from four wild isolates (JU1511, JU1926, JU1931, and JU1941) in the nematode Caenorhabditis elegans. We used RNA-seq to investigate how multiple alleles affect gene expression in these mpRILs. We found 1789 genes differentially expressed between the parental lines. Transgression, expression beyond any of the parental lines in the mpRILs, was found for 7896 genes. For expression QTL mapping almost 9000 SNPs were available. By combining these SNPs and the RNA-seq profiles of the mpRILs, we detected almost 6800 eQTLs. Most trans-eQTLs (63%) co-locate in six newly identified trans-bands. The trans-eQTLs found in previous two-parental allele eQTL experiments and this study showed some overlap (17.5-46.8%), highlighting on the one hand that a large group of genes is affected by polymorphic regulators across populations and conditions, on the other hand, it shows that the mpRIL population allows identification of novel gene expression regulatory loci. Taken together, the analysis of our mpRIL population provides a more refined insight into C. elegans complex trait genetics and eQTLs in general, as well as a starting point to further test and develop advanced statistical models for detection of multiallelic eQTLs and systems genetics studying the genotype-phenotype relationship.

Virus infection modulates male sexual behaviour in Caenorhabditis elegans.

Mating dynamics follow from natural selection on mate choice and individuals maximizing their reproductive success. Mate discrimination reveals itself by a plethora of behaviours and morphological characteristics, each of which can be affected by pathogens. A key question is how pathogens affect mate choice and outcrossing behaviour. Here we investigated the effect of Orsay virus on the mating dynamics of the androdiecious (male and hermaphrodite) nematode Caenorhabditis elegans. We tested genetically distinct strains and found that viral susceptibility differed between sexes in a genotype-dependent manner with males of reference strain N2 being more resistant than hermaphrodites. Males displayed a constitutively higher expression of intracellular pathogen response (IPR) genes, whereas the antiviral RNAi response did not have increased activity in males. Subsequent monitoring of sex ratios over 10 generations revealed that viral presence can change mating dynamics in isogenic populations. Sexual attraction assays showed that males preferred mating with uninfected rather than infected hermaphrodites. Together our results illustrate for the first time that viral infection can significantly affect male mating choice and suggest altered mating dynamics as a novel cause benefitting outcrossing under pathogenic stress conditions in C. elegans.

Heat Stress Reduces the Susceptibility of Caenorhabditis elegans to Orsay Virus Infection.

The nematode Caenorhabditis elegans has been a versatile model for understanding the molecular responses to abiotic stress and pathogens. In particular, the response to heat stress and virus infection has been studied in detail. The Orsay virus (OrV) is a natural virus of C. elegans and infection leads to intracellular infection and proteostatic stress, which activates the intracellular pathogen response (IPR). IPR related gene expression is regulated by the genes pals-22 and pals-25, which also control thermotolerance and immunity against other natural pathogens. So far, we have a limited understanding of the molecular responses upon the combined exposure to heat stress and virus infection. We test the hypothesis that the response of C. elegans to OrV infection and heat stress are co-regulated and may affect each other. We conducted a combined heat-stress-virus infection assay and found that after applying heat stress, the susceptibility of C. elegans to OrV was decreased. This difference was found across different wild types of C. elegans. Transcriptome analysis revealed a list of potential candidate genes associated with heat stress and OrV infection. Subsequent mutant screens suggest that pals-22 provides a link between viral response and heat stress, leading to enhanced OrV tolerance of C. elegans after heat stress.

Transcriptional analysis of the response of C. elegans to ethanol exposure.

Ethanol-induced transcriptional changes underlie important physiological responses to ethanol that are likely to contribute to the addictive properties of the drug. We examined the transcriptional responses of Caenorhabditis elegans across a timecourse of ethanol exposure, between 30 min and 8 h, to determine what genes and genetic pathways are regulated in response to ethanol in this model. We found that short exposures to ethanol (up to 2 h) induced expression of metabolic enzymes involved in metabolizing ethanol and retinol, while longer exposure (8 h) had much more profound effects on the transcriptome. Several genes that are known to be involved in the physiological response to ethanol, including direct ethanol targets, were regulated at 8 h of exposure. This longer exposure to ethanol also resulted in the regulation of genes involved in cilia function, which is consistent with an important role for the effects of ethanol on cilia in the deleterious effects of chronic ethanol consumption in humans. Finally, we found that food deprivation for an 8-h period induced gene expression changes that were somewhat ameliorated by the presence of ethanol, supporting previous observations that worms can use ethanol as a calorie source.

Punctuated Loci on Chromosome IV Determine Natural Variation in Orsay Virus Susceptibility of Caenorhabditis elegans Strains Bristol N2 and Hawaiian CB4856.

Host-pathogen interactions play a major role in evolutionary selection and shape natural genetic variation. The genetically distinct Caenorhabditis elegans strains, Bristol N2 and Hawaiian CB4856, are differentially susceptible to the Orsay virus (OrV). Here, we report the dissection of the genetic architecture of susceptibility to OrV infection. We compare OrV infection in the relatively resistant wild-type CB4856 strain to the more susceptible canonical N2 strain. To gain insight into the genetic architecture of viral susceptibility, 52 fully sequenced recombinant inbred lines (CB4856 × N2 RILs) were exposed to OrV. This led to the identification of two loci on chromosome IV associated with OrV resistance. To verify the two loci and gain additional insight into the genetic architecture controlling virus infection, introgression lines (ILs) that together cover chromosome IV, were exposed to OrV. Of the 27 ILs used, 17 had an CB4856 introgression in an N2 background, and 10 had an N2 introgression in a CB4856 background. Infection of the ILs confirmed and fine-mapped the locus underlying variation in OrV susceptibility, and we found that a single nucleotide polymorphism in cul-6 may contribute to the difference in OrV susceptibility between N2 and CB4856. An allele swap experiment showed the strain CB4856 became as susceptible as the N2 strain by having an N2 cul-6 allele, although having the CB4856 cul-6 allele did not increase resistance in N2. In addition, we found that multiple strains with nonoverlapping introgressions showed a distinct infection phenotype from the parental strain, indicating that there are punctuated locations on chromosome IV determining OrV susceptibility. Thus, our findings reveal the genetic complexity of OrV susceptibility in C. elegans and suggest that viral susceptibility is governed by multiple genes.IMPORTANCE Genetic variation determines the viral susceptibility of hosts. Yet, pinpointing which genetic variants determine viral susceptibility remains challenging. Here, we have exploited the genetic tractability of the model organism Caenorhabditis elegans to dissect the genetic architecture of Orsay virus infection. Our results provide novel insight into natural determinants of Orsay virus infection.

Metabolomics and lipidomics in Caenorhabditis elegans using a single-sample preparation.

Comprehensive metabolomic and lipidomic mass spectrometry methods are in increasing demand; for instance, in research related to nutrition and aging. The nematode Caenorhabditis elegans is a key model organism in these fields, owing to the large repository of available C. elegans mutants and their convenient natural lifespan. Here, we describe a robust and sensitive analytical method for the semi-quantitative analysis of >100 polar (metabolomics) and >1000 apolar (lipidomics) metabolites in C. elegans, using a single-sample preparation. Our method is capable of reliably detecting a wide variety of biologically relevant metabolic aberrations in, for example, glycolysis and the tricarboxylic acid cycle, pyrimidine metabolism and complex lipid biosynthesis. In conclusion, we provide a powerful analytical tool that maximizes metabolic data yield from a single sample. This article has an associated First Person interview with the joint first authors of the paper.

Balancing Selection of the Intracellular Pathogen Response in Natural Caenorhabditis elegans Populations.

Genetic variation in host populations may lead to differential viral susceptibilities. Here, we investigate the role of natural genetic variation in the Intracellular Pathogen Response (IPR), an important antiviral pathway in the model organism Caenorhabditis elegans against Orsay virus (OrV). The IPR involves transcriptional activity of 80 genes including the pals-genes. We examine the genetic variation in the pals-family for traces of selection and explore the molecular and phenotypic effects of having distinct pals-gene alleles. Genetic analysis of 330 global C. elegans strains reveals that genetic diversity within the IPR-related pals-genes can be categorized in a few haplotypes worldwide. Importantly, two key IPR regulators, pals-22 and pals-25, are in a genomic region carrying signatures of balancing selection, suggesting that different evolutionary strategies exist in IPR regulation. We infected eleven C. elegans strains that represent three distinct pals-22 pals-25 haplotypes with Orsay virus to determine their susceptibility. For two of these strains, N2 and CB4856, the transcriptional response to infection was also measured. The results indicate that pals-22 pals-25 haplotype shapes the defense against OrV and host genetic variation can result in constitutive activation of IPR genes. Our work presents evidence for balancing genetic selection of immunity genes in C. elegans and provides a novel perspective on the functional diversity that can develop within a main antiviral response in natural host populations.

Helminth Glycans at the Host-Parasite Interface and Their Potential for Developing Novel Therapeutics.

Helminths are parasitic worms that have successfully co-evolved with their host immune system to sustain long-term infections. Their successful parasitism is mainly facilitated by modulation of the host immune system via the release of excretory-secretory (ES) products covered with glycan motifs such as Lewis X, fucosylated LDN, phosphorylcholine and tyvelose. Evidence is accumulating that these glycans play key roles in different aspects of helminth infection including interactions with immune cells for recognition and evasion of host defences. Moreover, antigenic properties of glycans can be exploited for improving the efficacy of anti-helminthic vaccines. Here, we illustrate that glycans have the potential to open new avenues for the development of novel biopharmaceuticals and effective vaccines based on helminth glycoproteins.

Dissecting the eQTL Micro-Architecture in Caenorhabditis elegans.

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.

Genetic Variation in Complex Traits in Transgenic α-Synuclein Strains of Caenorhabditis elegans.

Different genetic backgrounds can modify the effect of mutated genes. Human α-synuclein (SNCA) gene encodes α-synuclein, and its oligomeric complexes accumulate with age and mediate the disruption of cellular homeostasis, resulting in the neuronal death that is characteristic of Parkinson's Disease. Polymorphic variants modulate this complex pathologic mechanism. Previously, we constructed five transgenic introgression lines of a Caenorhabditis elegans model of α-synuclein using genetic backgrounds that are genetically diverse from the canonical wild-type Bristol N2. A gene expression analysis revealed that the α-synuclein transgene differentially affects genome-wide transcription due to background modifiers. To further investigate how complex traits are affected in these transgenic lines, we measured the α-synuclein transgene expression, the overall accumulation of the fusion protein of α-synuclein and yellow fluorescent protein (YFP), the lysosome-related organelles, and the body size. By using quantitative PCR (qPCR), we demonstrated stable and similar expression levels of the α-synuclein transgene in different genetic backgrounds. Strikingly, we observed that the levels of the a-synuclein:YFP fusion protein vary in different genetic backgrounds by using the COPAS™ biosorter. The quantification of the Nile Red staining assay demonstrates that α-synuclein also affects lysosome-related organelles and body size. Our results show that the same α-synuclein introgression in different C. elegans backgrounds can produces differing effects on complex traits due to background modifiers.

Genetic Variation in Caenorhabditis elegans Responses to Pathogenic Microbiota.

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.

WormQTL2: an interactive platform for systems genetics in Caenorhabditis elegans.

Quantitative genetics provides the tools for linking polymorphic loci to trait variation. Linkage analysis of gene expression is an established and widely applied method, leading to the identification of expression quantitative trait loci (eQTLs). (e)QTL detection facilitates the identification and understanding of the underlying molecular components and pathways, yet (e)QTL data access and mining often is a bottleneck. Here, we present WormQTL2, a database and platform for comparative investigations and meta-analyses of published (e)QTL data sets in the model nematode worm C. elegans. WormQTL2 integrates six eQTL studies spanning 11 conditions as well as over 1000 traits from 32 studies and allows experimental results to be compared, reused and extended upon to guide further experiments and conduct systems-genetic analyses. For example, one can easily screen a locus for specific cis-eQTLs that could be linked to variation in other traits, detect gene-by-environment interactions by comparing eQTLs under different conditions, or find correlations between QTL profiles of classical traits and gene expression. WormQTL2 makes data on natural variation in C. elegans and the identified QTLs interactively accessible, allowing studies beyond the original publications. Database URL: www.bioinformatics.nl/WormQTL2/.

Transcriptome resilience predicts thermotolerance in Caenorhabditis elegans.

BACKGROUND: The detrimental effects of a short bout of stress can persist and potentially turn lethal, long after the return to normal conditions. Thermotolerance, which is the capacity of an organism to withstand relatively extreme temperatures, is influenced by the response during stress exposure, as well as the recovery process afterwards. While heat-shock response mechanisms have been studied intensively, predicting thermal tolerance remains a challenge. RESULTS: Here, we use the nematode Caenorhabditis elegans to measure transcriptional resilience to heat stress and predict thermotolerance. Using principal component analysis in combination with genome-wide gene expression profiles collected in three high-resolution time series during control, heat stress, and recovery conditions, we infer a quantitative scale capturing the extent of stress-induced transcriptome dynamics in a single value. This scale provides a basis for evaluating transcriptome resilience, defined here as the ability to depart from stress-expression dynamics during recovery. Independent replication across multiple highly divergent genotypes reveals that the transcriptional resilience parameter measured after a spike in temperature is quantitatively linked to long-term survival after heat stress. CONCLUSION: Our findings imply that thermotolerance is an intrinsic property that pre-determines long-term outcome of stress and can be predicted by the transcriptional resilience parameter. Inferring the transcriptional resilience parameters of higher organisms could aid in evaluating rehabilitation strategies after stresses such as disease and trauma.