Pharmacogenetic Analysis of Nicotine and Caffeine Resistance in Drosophila Melanogaster.

Abstract

Drug response is a polygenic trait that varies as a result of many factors, including the rate of drug absorption, metabolism and secretion. It is an important trait that can result in physiological and behavioral changes and can affect both health and survival. Associations between drug response and genes have been suggested but no clear picture of the relationship between genetic and pharmacological variation has yet emerged. Dissection of the genetic architecture of drug resistance is further complicated in that it involves the activity of multiple genes, which can interact with each other and the environment. My research uses Drosophila melanogaster to study resistance to the behaviorally active substances nicotine and caffeine. Both of these substances can exhibit adverse health effects at high doses or after chronic use by humans and are lethal when added to the diet of Drosophila.

For this study, several approaches were used to study drug response, including an analysis of quantitative genetic variation for drug resistance in natural populations, a P-element mutagenesis screen and association tests with candidate genes. These were used to assess drug resistance by measuring survival time on diets containing either nicotine or caffeine, and revealed that abundant genetic variation exists for drug resistance in Drosophila. This variation involves a complex genetic architecture and the interaction of many genes. Nevertheless, a classical forward genetic mutagenesis screen identified individual genes involved in drug resistance. These genes were not those typically studied for drug resistance, such as those in neurotransmitter systems and drug metabolism, but were involved in the development of the CNS and neuronal differentiation. Furthermore, an association study between nicotine and caffeine resistance and single nucleotide polymorphisms in three serotonin receptor genes, 5-HT1A, 5-HT1B and 5-HT2 detected significant associations between a SNP and nicotine resistance in the 5-HT1A gene. This suggests that although drug resistance is a complicated trait involving the interaction of many genes and environmental effects, mutations in individual genes and naturally occurring polymorphisms affecting survival time upon chronic exposure to nicotine and caffeine can be detected in Drosophila.