Abstract
Although most genetic association studies are performed with the intention of detecting nucleotide polymorphisms that are correlated with a complex trait, transcript abundance should also be expected to associate with diseases or phenotypes. We performed a scan for such quantitative trait transcripts in adult female heads of the fruit fly (Drosophila melanogaster) that might explain variation for nicotine resistance. The strongest association was seen for abundance of ornithine aminotransferase transcripts, implicating detoxification and neurotransmitter biosynthesis as mediators of the quantitative response to the drug. Subsequently, genetic analysis and metabolite profiling confirmed a complex role for ornithine and GABA levels in modification of survival time upon chronic nicotine exposure. Differences between populations from North Carolina and California suggest that the resistance mechanism may be an evolved response to environmental exposure.
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Acknowledgements
We thank S. Nuzhdin for providing the California inbred lines and R. Carrillo for initial sampling of nicotine resistance. This paper is dedicated to the memory of R. Rose, who first pointed out the lindane connection in our data. This work was supported by US National Institutes of Health grant P01-GM45344 to G.G.
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G.P.-G. performed all of the data analysis and experimental components, with the exception of the genetic complementation test (P.H.) and metabolite profiling (N.D.). She was assisted by W.-P.H. in the statistical analysis. G.G. conceived the experiment and wrote the manuscript.
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Supplementary information
Supplementary Fig. 1
Schematic of OAT function. (PDF 12 kb)
Supplementary Fig. 2
Regression of nicotine concentration on survival time. (PDF 14 kb)
Supplementary Fig. 3
qRT-PCR of Gad1. (PDF 10 kb)
Supplementary Table 1
Expression on nicotine correlated to survival time. (PDF 15 kb)
Supplementary Table 2
Expression on control food correlated to survival time. (PDF 14 kb)
Supplementary Table 3
Primers. (PDF 9 kb)
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Passador-Gurgel, G., Hsieh, WP., Hunt, P. et al. Quantitative trait transcripts for nicotine resistance in Drosophila melanogaster. Nat Genet 39, 264–268 (2007). https://doi.org/10.1038/ng1944
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DOI: https://doi.org/10.1038/ng1944
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