Abstract
Lead exposure has long been one of the most important topics in global public health because it is a potent developmental neurotoxin. Here, an eQTL analysis, which is the genome-wide association analysis of genetic variants with gene expression, was performed. In this analysis, the male heads of 79 Drosophila melanogaster inbred lines from Drosophila Synthetic Population Resource (DSPR) were treated with or without developmental exposure, from hatching to adults, to 250 μM lead acetate [Pb(C2H3O2)2]. The goal was to identify genomic intervals that influence the gene-expression response to lead. After detecting 1798 cis-eQTLs and performing an initial trans-eQTL analysis, we focused our analysis on lead-sensitive “trans-eQTL hotspots,” defined as genomic regions that are associated with a cluster of genes in a lead-dependent manner. We noticed that the genes associated with one of the 14 detected trans-eQTL hotspots, Chr 2L: 6,250,000 could be roughly divided into two groups based on their differential expression profile patterns and different categories of function. This trans-eQTL hotspot validates one identified in a previous study using different recombinant inbred lines. The expression of all the associated genes in the trans-eQTL hotspot was visualized with hierarchical clustering analysis. Besides the overall expression profile patterns, the heatmap displayed the segregation of differential parental genetic contributions. This suggested that trans-regulatory regions with different genetic contributions from the parental lines have significantly different expression changes after lead exposure. We believe this study confirms our earlier study, and provides important insights to unravel the genetic variation in lead susceptibility in Drosophila model.
Highlights
Expression QTLsOne of the biggest challenges in biology is to understand how genetic variation alters gene expression, which is known as genetical genomics (Mackay et al, 2009; Massouras et al, 2012; Lagarrigue et al, 2013)
In order to further understand and validate the trans-Expression QTLs (eQTLs) hotspots detected in our 2009 microarray paper on the neurotoxicity of lead in Drosophila (Ruden et al, 2009), we collected RNA-seq data from the heads of 79 recombinant inbred lines (RILs) selected from the Drosophila Synthetic Population Resource (DSPR) (King et al, 2012b)
The lines were initiated with eight parental strains A1–A8 that are from different geographic origins and should include a good mix of genetic variation in the Drosophila species which were intercrossed for 50 generations and inbred for another 25 (King et al, 2012b)
Summary
Expression QTLs (eQTLs)One of the biggest challenges in biology is to understand how genetic variation alters gene expression, which is known as genetical genomics (Mackay et al, 2009; Massouras et al, 2012; Lagarrigue et al, 2013). Cis-eQTLs tend to be “local”—near the locus of the gene encoding the regulated transcript, while trans-eQTLs tend to be “distant”—away from the locus of the regulator (Hirsch et al, 2003; Joo et al, 2014). Several disease-specific ciseQTLs were detected, one of which proved the correlation between a statin-related eQTL for the gene GATM (glycine amidinotransferase), that encodes the rate-limiting enzyme in creatine synthesis, and statin-induced myopathy (Mangravite et al, 2013)
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