Dataset Information

Lead Modulates trans- and cis-Expression Quantitative Trait Loci (eQTLs) in Drosophila melanogaster Heads.

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 ?M 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.

SUBMITTER: Qu W

PROVIDER: S-EPMC6158337 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Lead Modulates trans- and cis-Expression Quantitative Trait Loci (eQTLs) in Drosophila melanogaster Heads.

Qu Wen W Gurdziel Katherine K Pique-Regi Roger R Ruden Douglas M DM

Frontiers in genetics 20180920

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 ace ...[more]

PMID: 30294342

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Project description:Lead (Pb) poisoning has been a major public health issue globally and the recent Flint water crisis has drawn nation-wide attention to its effects. To better understand how lead plays a role as a neurotoxin, we utilized the Drosophila melanogaster model to study the genetic effects of lead exposure during development and identified lead-responsive genes. In our previous studies, we have successfully identified hundreds of lead-responsive expression QTLs (eQTLs) by using RNA-seq analysis on heads collected from the Drosophila Synthetic Population Resource. Cis-eQTLs, also known as allele-specific expression (ASE) polymorphisms, are generally single-nucleotide polymorphisms in the promoter regions of genes that affect expression of the gene, such as by inhibiting the binding of transcription factors. Trans-eQTLs are genes that regulate mRNA levels for many genes, and are generally thought to be SNPs in trans-acting transcription or translation factors. In this study, we focused our attention on alternative splicing events that are affected by lead exposure. Splicing QTLs (sQTLs), which can be caused by SNPs that alter splicing or alternative splicing (AS), such as by changing the sequence-specific binding affinity of splicing factors to the pre-mRNA. We applied two methods in search for sQTLs by using RNA-seq data from control and lead-exposed w1118Drosophila heads. First, we used the fraction of reads in a gene that falls in each exon as the phenotype. Second, we directly compared the transcript counts among the various splicing isoforms as the phenotype. Among the 1,236 potential Pb-responsive sQTLs (p < 0.0001, FDR < 0.39), mostly cis-sQTLs, one of the most distinct genes is Dscam1 (Down Syndrome Cell Adhesion Molecule), which has over 30,000 potential alternative splicing isoforms. We have also identified a candidate Pb-responsive trans-sQTL hotspot that appears to regulate 129 genes that are enriched in the "cation channel" gene ontology category, suggesting a model in which alternative splicing of these channels might lead to an increase in the elimination of Pb2+ from the neurons encoding these channels. To our knowledge, this is the first paper that uses sQTL analyses to understand the neurotoxicology of an environmental toxin in any organism, and the first reported discovery of a candidate trans-sQTL hotspot.

Dataset Information

Lead Modulates trans- and cis-Expression Quantitative Trait Loci (eQTLs) in Drosophila melanogaster Heads.

Publications

Lead Modulates <i>trans-</i> and <i>cis-</i>Expression Quantitative Trait Loci (eQTLs) in <i>Drosophila melanogaster</i> Heads.

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