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Identifying Loci Contributing to Natural Variation in Xenobiotic Resistance in Drosophila.

ABSTRACT: Natural populations exhibit a great deal of interindividual genetic variation in the response to toxins, exemplified by the variable clinical efficacy of pharmaceutical drugs in humans, and the evolution of pesticide resistant insects. Such variation can result from several phenomena, including variable metabolic detoxification of the xenobiotic, and differential sensitivity of the molecular target of the toxin. Our goal is to genetically dissect variation in the response to xenobiotics, and characterize naturally-segregating polymorphisms that modulate toxicity. Here, we use the Drosophila Synthetic Population Resource (DSPR), a multiparent advanced intercross panel of recombinant inbred lines, to identify QTL (Quantitative Trait Loci) underlying xenobiotic resistance, and employ caffeine as a model toxic compound. Phenotyping over 1,700 genotypes led to the identification of ten QTL, each explaining 4.5-14.4% of the broad-sense heritability for caffeine resistance. Four QTL harbor members of the cytochrome P450 family of detoxification enzymes, which represent strong a priori candidate genes. The case is especially strong for Cyp12d1, with multiple lines of evidence indicating the gene causally impacts caffeine resistance. Cyp12d1 is implicated by QTL mapped in both panels of DSPR RILs, is significantly upregulated in the presence of caffeine, and RNAi knockdown robustly decreases caffeine tolerance. Furthermore, copy number variation at Cyp12d1 is strongly associated with phenotype in the DSPR, with a trend in the same direction observed in the DGRP (Drosophila Genetic Reference Panel). No additional plausible causative polymorphisms were observed in a full genomewide association study in the DGRP, or in analyses restricted to QTL regions mapped in the DSPR. Just as in human populations, replicating modest-effect, naturally-segregating causative variants in an association study framework in flies will likely require very large sample sizes.

SUBMITTER: Najarro MA

PROVIDER: S-EPMC4664282 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Identifying Loci Contributing to Natural Variation in Xenobiotic Resistance in Drosophila.

Najarro Michael A MA Hackett Jennifer L JL Smith Brittny R BR Highfill Chad A CA King Elizabeth G EG Long Anthony D AD Macdonald Stuart J SJ

PLoS genetics 20151130 11

Natural populations exhibit a great deal of interindividual genetic variation in the response to toxins, exemplified by the variable clinical efficacy of pharmaceutical drugs in humans, and the evolution of pesticide resistant insects. Such variation can result from several phenomena, including variable metabolic detoxification of the xenobiotic, and differential sensitivity of the molecular target of the toxin. Our goal is to genetically dissect variation in the response to xenobiotics, and cha ...[more]

PMID: 26619284

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Project description:Closely-related, and otherwise morphologically similar insect species frequently show striking divergence in the shape and/or size of male genital structures, a phenomenon thought to be driven by sexual selection. Comparative interspecific studies can help elucidate the evolutionary forces acting on genital structures to drive this rapid differentiation. However, genetic dissection of sexual trait divergence between species is frequently hampered by the difficulty generating interspecific recombinants. Intraspecific variation can be leveraged to investigate the genetics of rapidly-evolving sexual traits, and here we carry out a genetic analysis of variation in the posterior lobe within D. melanogaster. The lobe is a male-specific process emerging from the genital arch of D. melanogaster and three closely-related species, is essential for copulation, and shows radical divergence in form across species. There is also abundant variation within species in the shape and size of the lobe, and while this variation is considerably more subtle than that seen among species, it nonetheless provides the raw material for QTL mapping. We created an advanced intercross population from a pair of phenotypically-different inbred strains, and after phenotyping and genotyping-by-sequencing the recombinants, mapped several QTL contributing to various measures of lobe morphology. The additional generations of crossing over in our mapping population led to QTL intervals that are smaller than is typical for an F2 mapping design. The intervals we map overlap with a pair of lobe QTL we previously identified in an independent mapping cross, potentially suggesting a level of shared genetic control of trait variation. Our QTL additionally implicate a suite of genes that have been shown to contribute to the development of the posterior lobe. These loci are strong candidates to harbor naturally-segregating sites contributing to phenotypic variation within D. melanogaster, and may also be those contributing to divergence in lobe morphology between species.

Dataset Information

Identifying Loci Contributing to Natural Variation in Xenobiotic Resistance in Drosophila.

Publications

Identifying Loci Contributing to Natural Variation in Xenobiotic Resistance in Drosophila.

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