No 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...

SummaryMany domestic breeds face challenges concerning genetic variability, because of their small population sizes along with a high risk of inbreeding. Therefore, it is important to obtain knowledge on their extinction risk, along with the possible benefits of certain breeding strategies. Since many domestic breeds face the same problems, results from such studies can be applied across breeds and species. Here a Population Viability Analysis (PVA) was implemented to simulate the future probability of extinction for a population of the endangered Danish Jutland cattle (Bos taurus), based on the software Vortex. A PVA evaluates the extinction risk of a population by including threats and demographic values. According to the results from the PVA the population will go extinct after 122 years with the current management. Four scenarios were created to investigate which changes in the breeding scheme would have the largest effect on the survival probabilities, including Scenario 1: More females in the breeding pool, scenario 2: More males in the breeding pool, scenario 3: Increased carrying capacity, and scenario 4: Supplementing males to the population through artificial insemination using semen from bulls used in the populations in past generations. All scenarios showed a positive effect on the population's probability of survival, and with a combination of the different scenarios, the population size seems to be stabilized.