title: Genome-wide association analysis of tolerance to methylmercury toxicity in Drosophila implicates myogenic and neuromuscular developmental pathways.
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.
authors.affiliation: Department of Environmental Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York, United States of America.
authors.forename: Sara L
authors.initials: SL
authors.lastname: Montgomery
authors.affiliation: Department of Environmental Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York, United States of America.
authors.forename: Daria
authors.initials: D
authors.lastname: Vorojeikina
authors.affiliation: Department of Biological Sciences, Genetics Program, and W. M. Keck Center for Behavioral Biology, North Carolina State University, Raleigh, North Carolina, United States of America.
authors.forename: Wen
authors.initials: W
authors.lastname: Huang
authors.affiliation: Department of Biological Sciences, Genetics Program, and W. M. Keck Center for Behavioral Biology, North Carolina State University, Raleigh, North Carolina, United States of America.
authors.forename: Trudy F C
authors.initials: TF
authors.lastname: Mackay
authors.affiliation: Department of Biological Sciences, Genetics Program, and W. M. Keck Center for Behavioral Biology, North Carolina State University, Raleigh, North Carolina, United States of America.
authors.forename: Robert R H
authors.initials: RR
authors.lastname: Anholt
authors.affiliation: Department of Environmental Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York, United States of America.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Rand
mesh_terms: D000818:Animals; D004331:Drosophila melanogaster / Q000187:drug effects / Q000235:genetics* / Q000254:growth & development*; D005260:Female; D063990:Gene Ontology; D053263:Gene Regulatory Networks / Q000187:drug effects; D055106:Genome-Wide Association Study; D006801:Humans; D007814:Larva / Q000187:drug effects / Q000235:genetics / Q000254:growth & development; D008767:Methylmercury Compounds / Q000633:toxicity*; D024510:Muscle Development / Q000187:drug effects* / Q000235:genetics*; D009420:Nervous System / Q000187:drug effects / Q000254:growth & development*; D010641:Phenotype; D011679:Pupa / Q000187:drug effects / Q000235:genetics / Q000254:growth & development
chemical_list: D008767:Methylmercury Compounds