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Genome-wide association analysis of tolerance to methylmercury toxicity in Drosophila implicates myogenic and neuromuscular developmental pathways.

Montgomery SL, Vorojeikina D, Huang W, Mackay TF, Anholt RR, Rand MD - PLoS ONE (2014)

Bottom Line: We found significant genetic variation in the effects of MeHg on development, measured by eclosion rate, giving a broad sense heritability of 0.86.We found that caffeine counteracts the deleterious effects of MeHg in the majority of lines, and there is significant genetic variance in the magnitude of this effect, with a broad sense heritability of 0.80.Furthermore, our observations that caffeine can ameliorate the toxic effects of MeHg show that nutritional factors and dietary manipulations may offer protection against the deleterious effects of MeHg exposure.

View Article: PubMed Central - PubMed

Affiliation: Department of Environmental Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York, United States of America.

ABSTRACT
Methylmercury (MeHg) is a persistent environmental toxin present in seafood that can compromise the developing nervous system in humans. The effects of MeHg toxicity varies among individuals, despite similar levels of exposure, indicating that genetic differences contribute to MeHg susceptibility. To examine how genetic variation impacts MeHg tolerance, we assessed developmental tolerance to MeHg using the sequenced, inbred lines of the Drosophila melanogaster Genetic Reference Panel (DGRP). We found significant genetic variation in the effects of MeHg on development, measured by eclosion rate, giving a broad sense heritability of 0.86. To investigate the influence of dietary factors, we measured MeHg toxicity with caffeine supplementation in the DGRP lines. We found that caffeine counteracts the deleterious effects of MeHg in the majority of lines, and there is significant genetic variance in the magnitude of this effect, with a broad sense heritability of 0.80. We performed genome-wide association (GWA) analysis for both traits, and identified candidate genes that fall into several gene ontology categories, with enrichment for genes involved in muscle and neuromuscular development. Overexpression of glutamate-cysteine ligase, a MeHg protective enzyme, in a muscle-specific manner leads to a robust rescue of eclosion of flies reared on MeHg food. Conversely, mutations in kirre, a pivotal myogenic gene identified in our GWA analyses, modulate tolerance to MeHg during development in accordance with kirre expression levels. Finally, we observe disruptions of indirect flight muscle morphogenesis in MeHg-exposed pupae. Since the pathways for muscle development are evolutionarily conserved, it is likely that the effects of MeHg observed in Drosophila can be generalized across phyla, implicating muscle as an additional hitherto unrecognized target for MeHg toxicity. Furthermore, our observations that caffeine can ameliorate the toxic effects of MeHg show that nutritional factors and dietary manipulations may offer protection against the deleterious effects of MeHg exposure.

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Overlap of genes identified by common polymorphic markers for variance in MeHg and MeHg+caffeine treatments.Candidate genes were identified from one or more associated polymorphisms in GWA analyses. A total of 145 and 106 genes were identified for MeHg and MeHg+caffeine, respectively. In common between the two treatments are 5 genes: pumilio, Synaptotagmin β, Glut4EF, pHCl, and CG9005.
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pone-0110375-g004: Overlap of genes identified by common polymorphic markers for variance in MeHg and MeHg+caffeine treatments.Candidate genes were identified from one or more associated polymorphisms in GWA analyses. A total of 145 and 106 genes were identified for MeHg and MeHg+caffeine, respectively. In common between the two treatments are 5 genes: pumilio, Synaptotagmin β, Glut4EF, pHCl, and CG9005.

Mentions: We found five genes in common between the two GWA analyses for exposure to MeHg in the presence or absence of caffeine: pumilio (pum, CG9755), Synaptotagmin β (Sytβ, CG42333), Glut4EF (CG34360), pHCl (CG44099) and CG9005 (Fig. 4). pum is an Armadillo repeat RNA binding protein involved in repression of translation and has two human homologs, PUM1 and PUM2. pum has functional implications in cellular and developmental processes including embryonic patterning, synaptic transmission, dendrite morphogenesis, pole cell migration, and learning and memory [28], [29]. Sytβ is one of seven Synaptotagmin family members in Drosophila with predicted function in synaptic vesicle exocytosis [30]. Sytβ localizes to the developing CNS as well as to specific motor neuron termini [31]. Glut4EF is a zinc finger transcription factor and homolog of the human glucose transporter (GLUT4) enhancer factor [32]. In flies, Glut4EF influences wing positioning with mutants giving a stretched out wing phenotype [32]. Mammalian Glut4EF is important for glucose uptake in muscles and associates with the MEF2A transcription factor [33]. pHCl encodes a gamma-aminobutyric acid A receptor, a ligand gated chloride channel that is expressed in the embryonic nervous system [34]. CG9005 encodes a protein of unknown function that has two human homologs, Hsap/KIAA1370 and Hsap/FAM214B. RNAi knockdown of CG9005 in flies has effects on development of the notum [35]. Therefore, four of the five overlapping genes share functions in the domain of neuromuscular function and neural development, suggesting that these biological processes are likely associated with MeHg tolerance during development.


Genome-wide association analysis of tolerance to methylmercury toxicity in Drosophila implicates myogenic and neuromuscular developmental pathways.

Montgomery SL, Vorojeikina D, Huang W, Mackay TF, Anholt RR, Rand MD - PLoS ONE (2014)

Overlap of genes identified by common polymorphic markers for variance in MeHg and MeHg+caffeine treatments.Candidate genes were identified from one or more associated polymorphisms in GWA analyses. A total of 145 and 106 genes were identified for MeHg and MeHg+caffeine, respectively. In common between the two treatments are 5 genes: pumilio, Synaptotagmin β, Glut4EF, pHCl, and CG9005.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4215868&req=5

pone-0110375-g004: Overlap of genes identified by common polymorphic markers for variance in MeHg and MeHg+caffeine treatments.Candidate genes were identified from one or more associated polymorphisms in GWA analyses. A total of 145 and 106 genes were identified for MeHg and MeHg+caffeine, respectively. In common between the two treatments are 5 genes: pumilio, Synaptotagmin β, Glut4EF, pHCl, and CG9005.
Mentions: We found five genes in common between the two GWA analyses for exposure to MeHg in the presence or absence of caffeine: pumilio (pum, CG9755), Synaptotagmin β (Sytβ, CG42333), Glut4EF (CG34360), pHCl (CG44099) and CG9005 (Fig. 4). pum is an Armadillo repeat RNA binding protein involved in repression of translation and has two human homologs, PUM1 and PUM2. pum has functional implications in cellular and developmental processes including embryonic patterning, synaptic transmission, dendrite morphogenesis, pole cell migration, and learning and memory [28], [29]. Sytβ is one of seven Synaptotagmin family members in Drosophila with predicted function in synaptic vesicle exocytosis [30]. Sytβ localizes to the developing CNS as well as to specific motor neuron termini [31]. Glut4EF is a zinc finger transcription factor and homolog of the human glucose transporter (GLUT4) enhancer factor [32]. In flies, Glut4EF influences wing positioning with mutants giving a stretched out wing phenotype [32]. Mammalian Glut4EF is important for glucose uptake in muscles and associates with the MEF2A transcription factor [33]. pHCl encodes a gamma-aminobutyric acid A receptor, a ligand gated chloride channel that is expressed in the embryonic nervous system [34]. CG9005 encodes a protein of unknown function that has two human homologs, Hsap/KIAA1370 and Hsap/FAM214B. RNAi knockdown of CG9005 in flies has effects on development of the notum [35]. Therefore, four of the five overlapping genes share functions in the domain of neuromuscular function and neural development, suggesting that these biological processes are likely associated with MeHg tolerance during development.

Bottom Line: We found significant genetic variation in the effects of MeHg on development, measured by eclosion rate, giving a broad sense heritability of 0.86.We found that caffeine counteracts the deleterious effects of MeHg in the majority of lines, and there is significant genetic variance in the magnitude of this effect, with a broad sense heritability of 0.80.Furthermore, our observations that caffeine can ameliorate the toxic effects of MeHg show that nutritional factors and dietary manipulations may offer protection against the deleterious effects of MeHg exposure.

View Article: PubMed Central - PubMed

Affiliation: Department of Environmental Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York, United States of America.

ABSTRACT
Methylmercury (MeHg) is a persistent environmental toxin present in seafood that can compromise the developing nervous system in humans. The effects of MeHg toxicity varies among individuals, despite similar levels of exposure, indicating that genetic differences contribute to MeHg susceptibility. To examine how genetic variation impacts MeHg tolerance, we assessed developmental tolerance to MeHg using the sequenced, inbred lines of the Drosophila melanogaster Genetic Reference Panel (DGRP). We found significant genetic variation in the effects of MeHg on development, measured by eclosion rate, giving a broad sense heritability of 0.86. To investigate the influence of dietary factors, we measured MeHg toxicity with caffeine supplementation in the DGRP lines. We found that caffeine counteracts the deleterious effects of MeHg in the majority of lines, and there is significant genetic variance in the magnitude of this effect, with a broad sense heritability of 0.80. We performed genome-wide association (GWA) analysis for both traits, and identified candidate genes that fall into several gene ontology categories, with enrichment for genes involved in muscle and neuromuscular development. Overexpression of glutamate-cysteine ligase, a MeHg protective enzyme, in a muscle-specific manner leads to a robust rescue of eclosion of flies reared on MeHg food. Conversely, mutations in kirre, a pivotal myogenic gene identified in our GWA analyses, modulate tolerance to MeHg during development in accordance with kirre expression levels. Finally, we observe disruptions of indirect flight muscle morphogenesis in MeHg-exposed pupae. Since the pathways for muscle development are evolutionarily conserved, it is likely that the effects of MeHg observed in Drosophila can be generalized across phyla, implicating muscle as an additional hitherto unrecognized target for MeHg toxicity. Furthermore, our observations that caffeine can ameliorate the toxic effects of MeHg show that nutritional factors and dietary manipulations may offer protection against the deleterious effects of MeHg exposure.

Show MeSH
Related in: MedlinePlus