Academic journal article Genetics

Fine-Mapping Nicotine Resistance Loci in Drosophila Using a Multiparent Advanced Generation Inter-Cross Population

Academic journal article Genetics

Fine-Mapping Nicotine Resistance Loci in Drosophila Using a Multiparent Advanced Generation Inter-Cross Population

Article excerpt

A routine part of life for all organisms is avoiding, and if necessary metabolizing, toxic substances encountered in the environment. A common challenge for animals are those toxins produced by potential prey and plant hosts as chemical defenses against predation and herbivory (Glendinning 2002, 2007). Understanding how organisms overcome these defenses can give us insight into the evolution of host special- ization, which can often involve an organism overcoming the defenses of a particular host, avoiding competition by making use of a resource toxic to other species (for example, Hungate et al. 2013). Many animals, especially insects, are also com- monly exposed to chemical pesticides used to protect crop plants. As a consequence of this strong evolutionary pressure, there are a number of examples of insecticide resistance aris- ing in natural populations (Crow 1957). Understanding the biology and molecular genetics underlying resistance to in- secticides (Perry et al. 2011; Ffrench-Constant 2013) is valu- able in the design of pest management strategies. In addition, humans are frequently exposed to an array of potentially harmful compounds, notably pharmaceuticals. Given the de- sire to achieve maximal drug efficacy while minimizing dos- age and avoiding adverse drug responses, elaborating the mechanisms of drug metabolism, and the genetic factors that affect it, is critically important for human health.

Animals use a cascade of enzymes to metabolize xenobi- otic compounds into less harmful substances (Xu et al. 2005; Li et al. 2007), and organisms possess many hundreds of genes whose products are involved in detoxification reac- tions. The best known class of phase I detoxification enzymes are the cytochrome P450 genes (P450s) that carry out oxida- tion, and other reactions on a broad range of compounds, typically decreasing their toxicity. The products of P450 reac- tions become the substrates for phase II enzymes, such as glutathione-S-transferases and UGTs. These enzymes add large, charged groups to substrate molecules, and the result- ing molecules are more hydrophilic, and thus more readily excreted. Finally, in phase III a range of membrane trans- porters, including ATP-binding cassette (ABC) transporters remove the conjugated products of phase II metabolism from the cell. Despite our general understanding of the series of molecular events involved in detoxification, hundreds of de- toxification genes have been identified in sequenced genomes (for instance, Strode et al. 2008; Chung et al. 2009; You et al. 2013), and for most xenobiotics the precise series of enzymes involved in their metabolism in vivo are unknown.

Here we sought to explore the genetic factors responsible for metabolic resistance to nicotine in the fruitfly. We are interested in nicotine for three broad reasons: First, nicotine is generated by a number of plant species, for example tobacco (Nicotiana sp.), as a defense against herbivory (Steppuhn et al. 2004). Nicotine presents a potent toxin to most herbivores, and only a few insect species are known to feed on nicotine-producing plants. Notably, the facultative tobacco specialist Manduca sexta (the tobacco hornworm) detoxifies ingested nicotine by inducing P450 enzymes (Snyder and Glendinning 1996). Second, nicotine has itself been used as an insecticide, and various pesticides that are chemically similar to nicotine-neonicotinoid pesticides-are in wide use (Goulson 2013). Third, nicotine is an extensively used addictive compound in humans, and nicotine dependence leads to a considerable number of tobacco-related, prevent- able deaths (Mokdad et al. 2004; Jha et al. 2013).

The elite model organism Drosophila has proven a valu- able system to understand the molecular genetics of drug responses (Kaun et al. 2012) and pesticide resistance (Perry et al. 2011). Indeed, one of the best described cases of the genetic control of xenobiotic resistance is the role of Cyp6g1 in resistance to the pesticide dichlorodiphenyltrichloro- ethane (DDT) in D. …

Search by... Author
Show... All Results Primary Sources Peer-reviewed

Oops!

An unknown error has occurred. Please click the button below to reload the page. If the problem persists, please try again in a little while.