The genetic architecture of the transcriptional response to heat-shock in C. elegans

The genetic architecture of the transcriptional response to heat-shock in C. elegans Mark G Sterken¹, L Basten Snoek¹, Roel P J Bevers¹, Rachel C Brenchley², Arjen E van 't Hof², Andrew R Cossins², Jan E Kammenga¹ 1Wageningen University, Laboratory of Nematology, Wageningen, 6708PB, Netherlands, 2University of Liverpool, Centre for Genomic Research, Liverpool, L69 7ZB, United Kingdom The basis for natural selection is variation and ultimately phenotypic variation is caused by differences between genotypes. Through genotypic variation organisms can be better equipped to handle (environmental) stress. This phenotypic plasticity, which is an important ability to cope with changing environmental conditions, can have a genetic source. However, most experimental work on C. elegans is conducted under ‘standard culturing conditions’ with a limited range of genotypes. Generally the genotypes used are restricted to wild type N2 and mutants in an N2 background, excluding detection of (more subtle) effects due to natural variation and differences in genetic background. Consequently, little is known about the variation in the components of genetic pathways within natural populations. Here, we investigated the influence of genetic variation on the transcriptional response to ambient heat-stress. Genetic variation between the genetically most divergent C. elegans isolates, N2 and CB4856, was perturbed and captured in a set of recombinant inbred lines (RILs) (Li et al., 2006). These RILs were exposed to a 2 hour heat-shock of 35oC. After which the genome- wide transcript levels were measured for all individual RILs. Quantitative trait locus mapping was applied to find the genomic loci that underlie the variation in transcriptional responses between the RILs. These heat-shock expression-QTLs (eQTLs) were compared to the eQTLs found in a control group that did not receive a heat-shock. Thereafter the experiment was independently repeated in an introgression line population, in which the lines only contain a single small introgression of CB4856 in an N2 background (Doroszuk et al. 2009). This allowed us to biologically validate the genotypic effects on gene expression found in the RIL population. We found that the genome-wide transcriptional response to heat-stress is highly regulated. Furthermore the regulated genes (those with an eQTL) and the location of the regulators were confirmed to a high degree in the introgression lines. This result provides a unique insight in the robustness of quantitative genetic analyses and shows the biologic relevance of its outcomes. Li et al. (2006) Plos Genetics 2(12): e222 Doroszuk et al. (2009) NAR 37: 16, e110 Funded by ERASysBio+ project GRAPPLE - Iterative modelling of gene regulatory interactions underlying stress, disease and ageing in C. elegans