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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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A shared functional network among non-overlapping genes identified in GWA of MeHg alone and MeHg+caffeine treatments.Network maps generated by GeneMANIA illustrate an example of a shared network for muscle structure development of genes identified in the GWA for MeHg alone (A) and MeHg+caffeine (B). Interactions are identified at the level of co-expression (purple lines), co-localization (blue lines), genetic interactions (green lines) and physical interactions (red lines). Query genes from the GWA analyses are represented by black circles and non-query genes (computationally recruited to complete network associations) are indicated by gray circles. The cluster of genes comprising the network is sorted to the inside of the circle, while the remaining query genes, not associated with the network, remain on the periphery.
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pone-0110375-g005: A shared functional network among non-overlapping genes identified in GWA of MeHg alone and MeHg+caffeine treatments.Network maps generated by GeneMANIA illustrate an example of a shared network for muscle structure development of genes identified in the GWA for MeHg alone (A) and MeHg+caffeine (B). Interactions are identified at the level of co-expression (purple lines), co-localization (blue lines), genetic interactions (green lines) and physical interactions (red lines). Query genes from the GWA analyses are represented by black circles and non-query genes (computationally recruited to complete network associations) are indicated by gray circles. The cluster of genes comprising the network is sorted to the inside of the circle, while the remaining query genes, not associated with the network, remain on the periphery.

Mentions: To assess to what extent genes associated with variation in MeHg tolerance can be assembled into genetic networks that represent biological pathways, we used the GeneMANIA [39] algorithm. The results from such analyses generate hypotheses regarding biological processes associated with phenotypic variation that can subsequently be tested by disrupting hub genes though mutational analyses or targeted RNAi. Although only five candidate genes overlapped between the MeHg alone versus MeHg+caffeine treatments, we found substantial enrichment for genes associated with a number of muscle development functions for MeHg treatment both with and without caffeine and an additional overlap for the functional category of receptor protein kinase signaling (Table 3). One of the resulting GeneMANIA functional categories is assigned the “muscle structure development” network term and is shown schematically in Figure 5A and B for MeHg alone and MeHg+caffeine, respectively. Genes on the query list that are enriched for the “muscle structure development” category under analysis are listed in Tables 4 and 5. Five core genes in the network derived from the GWA analysis of the effects of MeHg alone act in muscle cell fusion and muscle attachment and development: inflated (if, CG9623), kin of irre (kirre, a.k.a. dumbfounded (duf) CG3653), sticks and stones (sns, CG331441), kon-tiki (kon, CG10275) and rolling pebbles (rols, CG32096) (Fig. 5A and Table 4). Also of note are five genes that play a role in neuromuscular junction development and integrity; sugar free frosting (sff, CG6114), rae1 (CG9862), pum (CG9755), spinster (spin, CG8428) and Syndecan (Sdc, CG10497) (Fig. 5A and Table 4). Nine of these 15 genes have human homologs (Table 4). Among the 10 genes in the “muscle structure development” network with MeHg+caffeine treatments eight have human homologs (Table 5). It is of interest that eight of these 10 genes are transcriptionally responsive to caffeine (Table 5).


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)

A shared functional network among non-overlapping genes identified in GWA of MeHg alone and MeHg+caffeine treatments.Network maps generated by GeneMANIA illustrate an example of a shared network for muscle structure development of genes identified in the GWA for MeHg alone (A) and MeHg+caffeine (B). Interactions are identified at the level of co-expression (purple lines), co-localization (blue lines), genetic interactions (green lines) and physical interactions (red lines). Query genes from the GWA analyses are represented by black circles and non-query genes (computationally recruited to complete network associations) are indicated by gray circles. The cluster of genes comprising the network is sorted to the inside of the circle, while the remaining query genes, not associated with the network, remain on the periphery.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0110375-g005: A shared functional network among non-overlapping genes identified in GWA of MeHg alone and MeHg+caffeine treatments.Network maps generated by GeneMANIA illustrate an example of a shared network for muscle structure development of genes identified in the GWA for MeHg alone (A) and MeHg+caffeine (B). Interactions are identified at the level of co-expression (purple lines), co-localization (blue lines), genetic interactions (green lines) and physical interactions (red lines). Query genes from the GWA analyses are represented by black circles and non-query genes (computationally recruited to complete network associations) are indicated by gray circles. The cluster of genes comprising the network is sorted to the inside of the circle, while the remaining query genes, not associated with the network, remain on the periphery.
Mentions: To assess to what extent genes associated with variation in MeHg tolerance can be assembled into genetic networks that represent biological pathways, we used the GeneMANIA [39] algorithm. The results from such analyses generate hypotheses regarding biological processes associated with phenotypic variation that can subsequently be tested by disrupting hub genes though mutational analyses or targeted RNAi. Although only five candidate genes overlapped between the MeHg alone versus MeHg+caffeine treatments, we found substantial enrichment for genes associated with a number of muscle development functions for MeHg treatment both with and without caffeine and an additional overlap for the functional category of receptor protein kinase signaling (Table 3). One of the resulting GeneMANIA functional categories is assigned the “muscle structure development” network term and is shown schematically in Figure 5A and B for MeHg alone and MeHg+caffeine, respectively. Genes on the query list that are enriched for the “muscle structure development” category under analysis are listed in Tables 4 and 5. Five core genes in the network derived from the GWA analysis of the effects of MeHg alone act in muscle cell fusion and muscle attachment and development: inflated (if, CG9623), kin of irre (kirre, a.k.a. dumbfounded (duf) CG3653), sticks and stones (sns, CG331441), kon-tiki (kon, CG10275) and rolling pebbles (rols, CG32096) (Fig. 5A and Table 4). Also of note are five genes that play a role in neuromuscular junction development and integrity; sugar free frosting (sff, CG6114), rae1 (CG9862), pum (CG9755), spinster (spin, CG8428) and Syndecan (Sdc, CG10497) (Fig. 5A and Table 4). Nine of these 15 genes have human homologs (Table 4). Among the 10 genes in the “muscle structure development” network with MeHg+caffeine treatments eight have human homologs (Table 5). It is of interest that eight of these 10 genes are transcriptionally responsive to caffeine (Table 5).

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