Dataset Information

Genetic Signatures of Drug Response Variability in Drosophila melanogaster.

ABSTRACT: Knowledge of the genetic basis underlying variation in response to environmental exposures or treatments is important in many research areas. For example, knowing the set of causal genetic variants for drug responses could revolutionize personalized medicine. We used Drosophila melanogaster to investigate the genetic signature underlying behavioral variability in response to methylphenidate (MPH), a drug used in the treatment of attention-deficit/hyperactivity disorder. We exposed a wild-type D. melanogaster population to MPH and a control treatment, and observed an increase in locomotor activity in MPH-exposed individuals. Whole-genome transcriptomic analyses revealed that the behavioral response to MPH was associated with abundant gene expression alterations. To confirm these patterns in a different genetic background and to further advance knowledge on the genetic signature of drug response variability, we used a system of inbred lines, the Drosophila Genetic Reference Panel (DGRP). Based on the DGRP, we showed that the behavioral response to MPH was strongly genotype-dependent. Using an integrative genomic approach, we incorporated known gene interactions into the genomic analyses of the DGRP, and identified putative candidate genes for variability in drug response. We successfully validated 71% of the investigated candidate genes by gene expression knockdown. Furthermore, we showed that MPH has cross-generational behavioral and transcriptomic effects. Our findings establish a foundation for understanding the genetic mechanisms driving genotype-specific responses to medical treatment, and highlight the opportunities that integrative genomic approaches have in optimizing medical treatment of complex diseases.

SUBMITTER: Rohde PD

PROVIDER: S-EPMC6781897 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Genetic Signatures of Drug Response Variability in <i>Drosophila melanogaster</i>.

Rohde Palle Duun PD Jensen Iben Ravnborg IR Sarup Pernille Merete PM Ørsted Michael M Demontis Ditte D Sørensen Peter P Kristensen Torsten Nygaard TN

Genetics 20190827 2

Knowledge of the genetic basis underlying variation in response to environmental exposures or treatments is important in many research areas. For example, knowing the set of causal genetic variants for drug responses could revolutionize personalized medicine. We used <i>Drosophila melanogaster</i> to investigate the genetic signature underlying behavioral variability in response to methylphenidate (MPH), a drug used in the treatment of attention-deficit/hyperactivity disorder. We exposed a wild- ...[more]

PMID: 31455722

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Project description:Adaptation of complex traits depends on standing genetic variation at multiple loci. The allelic variants that have positive fitness effects, however, can differ depending on the genetic background and the selective pressure. Previously, we interrogated the Drosophila melanogaster genome at the population level for polymorphic positions and identified 215 single nucleotide polymorphisms (SNPs) that had significantly changed in frequency after experimental evolution for increased parasitoid resistance. In the current study, we follow up on 11 of these SNPs as putative targets of the experimental selection process (Jalvingh et al., 2014). We study the patterns of genetic variation for these SNPs in several European field populations. Furthermore, we associate the genetic variation of these SNPs to variation in resistance against the parasitoid Asobara tabida, by determining the individual phenotype and SNP genotype for 144 individuals from four Selection lines and four non-selected Control lines and for 400 individuals from 12 Field lines that differ in parasitoid resistance. For the Selection lines we additionally monitored the changes in allele frequencies throughout the five generations of experimental selection. For three genes, mbl (Zn-finger protein), mthl4 (G-protein coupled receptor) and CG17287 (protein-cysteine S-palmitoyltransferase) individual SNP genotypes were significantly associated with resistance level in the Selection and Control lines. Additionally, the minor allele in mbl and mthl4 were consistently and gradually favored throughout the five generations of experimental evolution. However, none of these alleles did appear to be associated to high resistance in the Field lines. We suggest that, within field populations, selection for parasitoid resistance is a gradual process that involves co-adapted gene complexes. Fast artificial selection, however, enforces the sudden cumulating of particular alleles that confer high resistance (genetic sweep). We discuss our findings in the context of local adaptation.

Dataset Information

Genetic Signatures of Drug Response Variability in Drosophila melanogaster.

Publications

Genetic Signatures of Drug Response Variability in <i>Drosophila melanogaster</i>.

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