Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Natural Genetic Variation Influences Protein Abundances in C. elegans Developmental Signalling Pathways

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 Bristol N2 and Hawaii CB4856 to enable quantitative trait loci (QTL) mapping. Variation in gene expression was greater in the RILs than in the parental lines, at the proteome as well as at the transcriptome levels. We detected a trans-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. Parental genotypes N2 (3x) and CB4856 (3x) and 47 RILs from (Li etal 2006; Vinuela etal 2010 and Elvin etal 2011)

ORGANISM(S): Caenorhabditis elegans

SUBMITTER: Basten Snoek

PROVIDER: E-GEOD-77905 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:The nutritional environments that organisms experience are inherently variable, requiring tight coordination of how resources are allocated to different functions relative to the total amount of resources available. A growing body of evidence supports the hypothesis that key endocrine pathways play a fundamental role in this coordination. In particular, the insulin/insulin-like growth factor signaling (IIS) and target of rapamycin (TOR) pathways have been implicated in nutrition-dependent changes in metabolism and nutrient allocation, however little is known about the genetic basis of standing variation in the pathways. To characterize natural genetic variation in the IIS/TOR pathway, we used over 250 recombinant inbred lines (RILs) derived from a multiparental mapping population, the Drosophila Synthetic Population Resource (DSPR), to map QTL for transcript levels of the genes encoding 52 of the core components of the IIS/TOR pathway in three different nutritional environments (dietary restriction, control, and high sugar). In addition, we assayed lifespan for 80 RILs in both dietary restriction and control diets. We identified cis (i.e., local) QTL for six transcripts, all of which are significant in multiple nutrient environments. Further, we identified trans (i.e., distant) QTL for two transcripts, specific to a single nutrient environment, and one “plasticity” QTL that influences the change in gene expression between the control and high sugar diet. Nearly all transcripts, 85%, were significantly differentially expressed between diets. A discriminant function analysis for the control and dietary restriction treatments identified which transcripts best predict the diet treatment. The resulting composite discriminant function scores are correlated with median lifespan (r = 0.45) and mapping these scores revealed a significant QTL within the dietary restriction diet. Our results corroborate the association between the IIS/TOR pathway and the increase in lifespan under dietary restriction in a natural population and identify new locations in the genome involved in regulating the IIS/TOR pathway.

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Natural Genetic Variation Influences Protein Abundances in C. elegans Developmental Signalling Pathways

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