The Genetic Basis for Variation in Sensitivity to Lead Toxicity in
            <i>Drosophila melanogaster</i>

Zhou, Shanshan; Morozova, Tatiana V.; Hussain, Yasmeen N.; Luoma, Sarah E.; McCoy, Lenovia J.; Yamamoto, Akihiko; Mackay, Trudy F. C.; Anholt, Robert R. H.

doi:10.1289/ehp.1510513

Cited by 42 publications

(36 citation statements)

References 39 publications

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“…The apparent inconsistency between these studies likely stems from the difference in methods to estimate realized heritability compared with H 2 and h 2 as defined above. Where methodically more comparable estimators were also applied to DGRP strains, it can be seen that pupation height choice is similar to the values estimated for other behaviour traits, for example, taste sensitivity to sugars (H 2 = 0.63) (Uchizono & Tanimura, 2017), sensitivity to lead toxicity (H 2 = 0.76) (Zhou et al, 2016), aggression (H 2 = 0.69) (Shorter et al, 2015), DDT resistance (H 2 = 0.8) (Schmidt et al, 2017) and adult foraging behaviour (h 2 = 0.52) (Lee et al, 2017).…”

Section: Discussionsupporting

confidence: 54%

Identification of a genetic network for an ecologically relevant behavioural phenotype in Drosophila melanogaster

2020

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Pupation site choice of Drosophila third‐instar larvae is critical for the survival of individuals, as pupae are exposed to various biotic and abiotic dangers while immobilized during the 3–4 days of metamorphosis. This singular behavioural choice is sensitive to both environmental and genetic factors. Here, we developed a high‐throughput phenotyping approach to assay the variation in pupation height in Drosophila melanogaster, while controlling for possibly confounding factors. We find substantial variation of mean pupation height among sampled natural stocks and we show that the Drosophila Genetic Reference Panel (DGRP) reflects this variation. Using the DGRP stocks for genome‐wide association (GWA) mapping, 16 loci involved in determining pupation height could be resolved. The candidate genes in these loci are enriched for high expression in the larval central nervous system. A genetic network could be constructed from the candidate loci, which places scribble (scrib) at the centre, plus other genes known to be involved in nervous system development, such as Epidermal growth factor receptor (Egfr) and p53. Using gene disruption lines, we could functionally validate several of the initially identified loci, as well as additional loci predicted from network analysis. Our study shows that the combination of high‐throughput phenotyping with a genetic analysis of variation captured from the wild can be used to approach the genetic dissection of an environmentally relevant behavioural phenotype.

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Section: Discussionsupporting

confidence: 54%

Identification of a genetic network for an ecologically relevant behavioural phenotype in Drosophila melanogaster

2020

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“…Enrichment of neurodevelopmental genes has been a hallmark of genome-wide studies on variation in behavioral traits, such as olfactory behavior (Swarup et al , 2013), and susceptibility to environmental toxins (Zhou et al , 2016). When we translated the Drosophila genetic interaction network into an orthologous human network, nine out of 30 input genes could be interconnected when we allowed two missing genes ( i.e .…”

Section: Discussionmentioning

confidence: 99%

Genetics of alcohol consumption in Drosophila melanogaster

Fochler

Morozova

Davis

et al. 2017

Genes Brain and Behavior

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Individual variation in alcohol consumption in human populations is determined by genetic, environmental, social and cultural factors. In contrast to humans, genetic contributions to complex behavioral phenotypes can be readily dissected in Drosophila, where both the genetic background and environment can be controlled and behaviors quantified through simple high-throughput assays. Here, we measured voluntary consumption of ethanol in ~3,000 individuals of each sex from an advanced intercross population derived from 37 lines of the Drosophila melanogaster Genetic Reference Panel. Extreme QTL mapping identified 385 differentially segregating allelic variants located in or near 291 genes at P < 10−8. The effects of single nucleotide polymorphisms associated with voluntary ethanol consumption are sex-specific, as found for other alcohol-related phenotypes. To assess causality we used RNAi knockdown or P[MiET1] mutants and their corresponding controls and functionally validated 86% of candidate genes in at least one sex. We constructed a genetic network comprised of 23 genes along with a separate trio and a pair of connected genes. Gene ontology analyses showed enrichment of developmental genes, including development of the nervous system. Furthermore, a network of human orthologs revealed enrichment for signal transduction processes, protein metabolism and developmental processes, including nervous system development. Our results show that the genetic architecture that underlies variation in voluntary ethanol consumption is sexually dimorphic and partially overlaps with genetic factors that control variation in feeding behavior and alcohol sensitivity. This integrative genetic architecture is rooted in evolutionarily conserved features that can be extrapolated to human genetic interaction networks.

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“…Previously, we performed a genome-wide association (GWA) analysis using the DGRP and identified polymorphisms associated with variation in sensitivity to lead toxicity by quantifying development time and viability [ 46 ]. Effects of lead exposure on adult locomotor activity have also been documented both by a QTL mapping study in recombinant inbred lines constructed from parental Oregon R and Russian 2b lines [ 47 ] and in the DGRP [ 46 ].…”

Section: Introductionmentioning

confidence: 99%

A Drosophila model for toxicogenomics: Genetic variation in susceptibility to heavy metal exposure

et al. 2017

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The genetic factors that give rise to variation in susceptibility to environmental toxins remain largely unexplored. Studies on genetic variation in susceptibility to environmental toxins are challenging in human populations, due to the variety of clinical symptoms and difficulty in determining which symptoms causally result from toxic exposure; uncontrolled environments, often with exposure to multiple toxicants; and difficulty in relating phenotypic effect size to toxic dose, especially when symptoms become manifest with a substantial time lag. Drosophila melanogaster is a powerful model that enables genome-wide studies for the identification of allelic variants that contribute to variation in susceptibility to environmental toxins, since the genetic background, environmental rearing conditions and toxic exposure can be precisely controlled. Here, we used extreme QTL mapping in an outbred population derived from the D. melanogaster Genetic Reference Panel to identify alleles associated with resistance to lead and/or cadmium, two ubiquitous environmental toxins that present serious health risks. We identified single nucleotide polymorphisms (SNPs) associated with variation in resistance to both heavy metals as well as SNPs associated with resistance specific to each of them. The effects of these SNPs were largely sex-specific. We applied mutational and RNAi analyses to 33 candidate genes and functionally validated 28 of them. We constructed networks of candidate genes as blueprints for orthologous networks of human genes. The latter not only provided functional contexts for known human targets of heavy metal toxicity, but also implicated novel candidate susceptibility genes. These studies validate Drosophila as a translational toxicogenomics gene discovery system.

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The Genetic Basis for Variation in Sensitivity to Lead Toxicity in Drosophila melanogaster

Cited by 42 publications

References 39 publications

Identification of a genetic network for an ecologically relevant behavioural phenotype in Drosophila melanogaster

Identification of a genetic network for an ecologically relevant behavioural phenotype in Drosophila melanogaster

Genetics of alcohol consumption in Drosophila melanogaster

A Drosophila model for toxicogenomics: Genetic variation in susceptibility to heavy metal exposure

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