From QTL to gene: C. elegans facilitates discoveries of the genetic mechanisms underlying natural variation.

Although many studies have examined quantitative trait variation across many species, only a small number of genes and thereby molecular mechanisms have been discovered. Without these data, we can only speculate about evolutionary processes that underlie trait variation. Here, we review how quantitative and molecular genetics in the nematode Caenorhabditis elegans led to the discovery and validation of 37 quantitative trait genes over the past 15 years. Using these data, we can start to make inferences about evolution from these quantitative trait genes, including the roles that coding versus noncoding variation, gene family expansion, common versus rare variants, pleiotropy, and epistasis play in trait variation across this species.

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.

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.