Access Type

Open Access Dissertation

Date of Award

January 2016

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Pharmacology

First Advisor

Douglas M. Ruden

Abstract

Lead exposure has long been one of the most important topics in global public health since it is a potent developmental neurotoxin. Here, we conducted an expression QTL (eQTLs) analysis, which is genome-wide association analysis of genetic variants with differential gene expression, in the male heads of 79 Drosophila melanogaster recombinant inbred lines originally from eight parental strains in the presence or absence of developmental exposure to 250 µM lead acetate. The aim was to study the effects of lead exposure on gene expression and identify the lead-responsive genes. After detecting 1,536 cis-eQTLs and 952 trans-eQTLs (1000 permutation threshold at 0.05), 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 13 detected trans-eQTL hotspots, Chr2L: 6,250,000 could be roughly divided into two groups based on their differential expression profile patterns and different categories of function. We visualized the expression of all the associated genes in the trans-eQTL hotspot with hierarchical clustering. Besides the overall expression profile patterns, the heat maps 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 that the lead-responsive trans-eQTL hotspots generated in this study could improve our understanding of genetic dissection of transcript abundance and provide insights into the mechanisms of how environmental toxins affect transcriptional pathways.

In a follow-up study, we also found lead-responsive sQTLs. The identification of lead-responsive sQTLs provides further evidence that different parental genomic contribution can cause significantly differential isoform usage after developmental lead exposure. Great achievements have been made in understanding how trans-sQTL hotspots alter the susceptibility to lead exposure, opening up a gate towards the mechanisms of trans-sQTL hotspots, as well as the neurotoxicity of lead.

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