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The genetic signature of variability in drug response in Drosophila melanogaster

ABSTRACT: Knowledge of the genetic mechanisms underlying among-individual variation in response to environmental variables or treatment is important in many research areas; for example, acquaintance of the set of causal genetic variants for drug responses could revolutionize the field of personalized medicine. We used Drosophila melanogaster to investigate the genetic signature underlying variability in response to methylphenidate (MPH), a drug used in treatment of ADHD. We exposed a wild type D. melanogaster population to MPH or a control treatment and observed an increase in locomotor activity in individuals exposed to MPH. 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 sequenced inbred lines, the Drosophila Genetic Reference Panel. Utilizing an integrative genomic approach we incorporated the transcriptomic data as well as gene interactions into the genomic analyses, from which we identified putative candidate genes for drug response variability. We successfully validated 70% of the investigated putative candidate genes by gene expression knockdown. Furthermore, we showed that MPH has cross generational behavioral- and transcriptomic effects.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE121643 | GEO | 2018/10/24

REPOSITORIES: GEO

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