Genetic Signatures of Drug Response Variability inDrosophila 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. KEYWORDS Ritalin; ADHD; Drosophila Genetic Reference Panel; cross-generational effects; locomotor activity U NDERSTANDING individual variability in response to treatment is one of the fundamental challenges in biological sciences. Treatment can be defined as any expected or unanticipated biotic or abiotic exposure; that is, any change in the environment of the organism, whether in the surrounding environment, such as temperature changes, or in the intrinsic environment, such as metabolic alterations caused by ingestion of chemicals. For many scientific fields-including medicine, animal and plant breeding, and evolutionary biology-knowledge of the mechanisms that underlie variability in how an individual responds to such treatment is important. This could, for example, involve predicting the consequences of climate change on species distribution, obtaining consistent output in livestock and plant breeding across heterogeneous production systems, or providing optimal treatment of conditions that require medical attention. The latter example was specifically investigated in the present study. Responses to pharmacological interventions are highly variable for many human diseases (Roden and George 2002). Personalized medicine has been proposed as a strategy to provide more accurate and effective medical treatm...

Genotype and Trait Specific Responses to Rapamycin Intake in Drosophila melanogaster

“…However, those two variants were not segregating among the six randomly chosen DGRP lines, and therefore we cannot assess the important of genetic variation within TOR for rapamycin response. Hence, the observed line-specific responses to rapamycin is not due to genetic variation within the TOR gene, but is likely caused by small effect variants distributed across many loci, which is consistent with the perception that drug-response phenotypes constitute complex quantitative genetic traits (as demonstrated by several DGRP studies [28,35,62,63]. Future studies using the DGRP can be useful for pinpointing the genetic architecture of rapamycin response and reveal putative genes responsible for the reaction to rapamycin treatment.…”

“…Additionally, sex specific responses, which are not investigated in this study, should be further investigated. The strong genotype by treatment interactions observed here, and in another recent study on Ritalin treatment using the DGRP lines [28] also highlight the need and potential for tailoring treatment to the individual patient guided by the genetic profile.…”

“…Using the DGRP lines for this purpose provide benefits because individuals from a given line are genome-wide homozygous meaning that a large number of genetically identical individuals can be tested across and within different treatments [24,25]. The DGRP system has been widely used to investigate the genetic basis of complex traits [26,27], and genotype by treatment interactions [28,[35][36][37], however, this is to our knowledge the first study using the DGRP system to investigate rapamycin intake. In accordance with previous findings from D. melanogaster we see a reduction of fecundity estimated by the number of eggs produced over a 72 h time period in flies exposed to rapamycin (Figure 2) [11,12].…”

“…The DGRP has been assessed for numerus traits and differ markedly in behavioural, morphological and life-history traits (see Review by Mackay and Huang (2018) [26], and Anholt and Mackay (2018) [27]). Further, lines from the DGRP have been shown to respond markedly different to drugs such as methylamphetamine [28]. These characteristics of the DGRP system and the fact that all lines are full genome sequenced make it an advantageous system for investigating the genetic architecture of complex traits and genotype by environment interactions.…”

Prediction of complex phenotypes using the Drosophila melanogaster metabolome

“…The DGRP genotypes, chromosomal inversions, Wolbachia infection status, and the phenotypic values for startle response, starvation resistance and chill coma recovery can be obtained from http://dgrp2.gnets.ncsu.edu/. The adjusted metabolome data can be found in the supplementary material and the locomotor activity measurements in the origical publication (Rohde et al 2019).…”