Abstract
Complex traits, including common disease-related traits, are affected by many different genes that function in multiple pathways and networks. The apoptosis, MAPK, Notch, and Wnt signalling pathways play important roles in development and disease progression. At the moment we have a poor understanding of how allelic variation affects gene expression in these pathways at the level of translation. Here we report the effect of natural genetic variation on transcript and protein abundance involved in developmental signalling pathways in Caenorhabditis elegans. We used selected reaction monitoring to analyse proteins from the abovementioned four pathways in a set of recombinant inbred lines (RILs) generated from the wild-type strains N2 (Bristol) and CB4856 (Hawaii) to enable quantitative trait locus (QTL) mapping. About half of the cases from the 44 genes tested showed a statistically significant change in protein abundance between various strains, most of these were however very weak (below 1.3-fold change). We detected a distant QTL on the left arm of chromosome II that affected protein abundance of the phosphatidylserine receptor protein PSR-1, and two separate QTLs that influenced embryonic and ionizing radiation-induced apoptosis on chromosome IV. Our results demonstrate that natural variation in C. elegans is sufficient to cause significant changes in signalling pathways both at the gene expression (transcript and protein abundance) and phenotypic levels.
Highlights
Most complex traits, including many common diseases such as cancer, neurodegenerative, and autoimmune diseases are affected by multiple genes
The extent of conservation in protein abundance in the dataset of the four signalling pathways is very similar to the variation that can be observed at the level of the whole proteome using stable isotope labelling by amino acids in cell culture (SILAC) based shotgun mass spectrometry data from [35] (Fig 1 and S4 Fig)
These observations suggest that for most of the measured proteins, the small variation in protein abundance observed between CB4856 and N2 is not due to genetic variation between the two strains, but rather comes from measurement errors or from the innate variation that exists between biological replicates of the same strain (S4 Fig)
Summary
Most complex traits, including many common diseases such as cancer, neurodegenerative, and autoimmune diseases are affected by multiple genes. To unravel how the genetic background affects signalling pathways that contribute to complex diseases, we used the model organism Caenorhabditis elegans [7]. Signalling pathways in C. elegans are usually studied in the canonical wild-type N2 (Bristol [20]) background through the screening for and characterization of induced mutations, which often lead to complete loss of gene function and show distinctive phenotypic defects. We quantified the abundances of selected proteins from four cancer signalling pathways (apoptosis, MAPK, Notch, and Wnt) using selected reaction monitoring (SRM), a mass spectrometric technique for targeted quantitative proteomics that is characterized by its high specificity, sensitivity, and wide dynamic range [32,33]. We measured apoptosis levels in both parental strains and RILs. We found that natural variation in C. elegans causes significant changes in signalling pathways both at the gene expression (transcript and protein abundance) and at the phenotypic levels
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