Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Quantitative trait transcripts for nicotine resistance in Drosophila melanogaster

Nature Genetics volume 39, pages 264–268 (2007)Cite this article

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Distribution of survival times on nicotine.
Figure 2: Regression of transcript abundance on survival time for CG8745.
Figure 3: Haploinsufficiency of CG8745e00991 for survival time on nicotine.
Figure 4: Regression of GABA and ornithine metabolites on survival time.

Similar content being viewed by others

References

  1. Liotta, L. & Petricoin, E. Molecular profiling of human cancer. Nat. Rev. Genet. 1, 48–56 (2000).

    Article  CAS  PubMed  Google Scholar 

  2. de Koning, D.J. & Haley, C.S. Genetical genomics in humans and model organisms. Trends Genet. 21, 377–381 (2005).

    Article  CAS  PubMed  Google Scholar 

  3. Mackay, T.F. The genetic architecture of quantitative traits. Annu. Rev. Genet. 35, 303–339 (2001).

    Article  CAS  PubMed  Google Scholar 

  4. Cohen, C., Welzl, H. & Battig, K. Effects of nicotine, caffeine and their combination on locomotor activity in rats. Pharmacol. Biochem. Behav. 40, 121–123 (1991).

    Article  CAS  PubMed  Google Scholar 

  5. Wolf, F.W. & Heberlein, U. Invertebrate models of drug abuse. J. Neurobiol. 54, 161–178 (2003).

    Article  CAS  PubMed  Google Scholar 

  6. Carrillo, R. & Gibson, G. Unusual genetic architecture of natural variation affecting drug resistance in Drosophila melanogaster. Genet. Res. 80, 205–213 (2002).

    Article  CAS  PubMed  Google Scholar 

  7. Jessen, A., Buemann, B., Toubro, S., Skovgaard, I.M. & Astrup, A. The appetite-suppressant effect of nicotine is enhanced by caffeine. Diabetes Obes. Metab. 7, 327–333 (2005).

    Article  CAS  PubMed  Google Scholar 

  8. Palsson, A. & Gibson, G. Association between nucleotide variation in Egfr and wing shape in Drosophila melanogaster. Genetics 167, 1187–1198 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Dworkin, I., Palsson, A., Birdsall, K. & Gibson, G. Evidence that Egfr contributes to cryptic genetic variation for photoreceptor determination in natural populations of Drosophila melanogaster. Curr. Biol. 13, 1888–1893 (2003).

    Article  CAS  PubMed  Google Scholar 

  10. Macdonald, S.J., Pastinen, T. & Long, A.D. The effect of polymorphisms in the Enhancer of split gene complex on bristle number variation in a large wild-caught cohort of Drosophila melanogaster. Genetics 171, 1741–1756 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. De Luca, M. et al. Dopa decarboxylase (Ddc) affects variation in Drosophila longevity. Nat. Genet. 34, 429–433 (2003).

    Article  CAS  PubMed  Google Scholar 

  12. Seiler, N. Ornithine aminotransferase, a potential target for the treatment of hyperammonemias. Curr. Drug Targets 1, 119–153 (2000).

    Article  CAS  PubMed  Google Scholar 

  13. Kelly, A. & Stanley, C.A. Disorders of glutamate metabolism. Ment. Retard. Dev. Disabil. Res. Rev. 7, 287–295 (2001).

    Article  CAS  PubMed  Google Scholar 

  14. Sivilotti, L. & Nistri, A. GABA receptor mechanisms in the central nervous system. Prog. Neurobiol. 36, 35–92 (1991).

    Article  CAS  PubMed  Google Scholar 

  15. Beleboni, R.O. et al. Pharmacological and biochemical aspects of GABAergic neurotransmission: pathological and neuropsychobiological relationships. Cell. Mol. Neurobiol. 24, 707–728 (2004).

    Article  CAS  PubMed  Google Scholar 

  16. Livak, K.J. & Schmittgen, T.D. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)). Methods 25, 402–408 (2001).

    Article  CAS  PubMed  Google Scholar 

  17. Vale, C., Damgaard, I., Sunol, C., Rodriguez-Farre, E. & Schousboe, A. Cytotoxic action of lindane in neocortical GABAergic neurons is primarily mediated by interaction with flunitrazepam-sensitive GABA(A) receptors. J. Neurosci. Res. 52, 276–285 (1998).

    Article  CAS  PubMed  Google Scholar 

  18. Parmar, D. et al. Effect of lindane on hepatic and brain cytochrome P450s and influence of P450 modulation in lindane induced neurotoxicity. Food Chem. Toxicol. 41, 1077–1087 (2003).

    Article  CAS  PubMed  Google Scholar 

  19. Tomfohr, J., Lu, J. & Kepler, T.B. Pathway level analysis of gene expression using singular value decomposition. BMC Bioinformatics 6, 225 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  20. Thibault, S.T. et al. A complementary transposon toolkit for Drosophila melanogaster using P and piggyBac. Nat. Genet. 36, 283–287 (2004).

    Article  CAS  PubMed  Google Scholar 

  21. Yoneda, Y., Roberts, E. & Dietz, G.W., Jr . A new synaptosomal biosynthetic pathway of glutamate and GABA from ornithine and its negative feedback inhibition by GABA. J. Neurochem. 38, 1686–1694 (1982).

    Article  CAS  PubMed  Google Scholar 

  22. Palsson, A., Rouse, A., Riley-Berger, R., Dworkin, I. & Gibson, G. Nucleotide variation in the Egfr locus of Drosophila melanogaster. Genetics 167, 1199–1212 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Yang, H.P. & Nuzhdin, S.V. Fitness costs of Doc expression are insufficient to stabilize its copy number in Drosophila melanogaster. Mol. Biol. Evol. 20, 800–804 (2003).

    Article  CAS  PubMed  Google Scholar 

  24. Jain, A.N. et al. Fully automatic quantification of microarray image data. Genome Res. 12, 325–332 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Churchill, G.A. Fundamentals of experimental design for cDNA microarrays. Nat. Genet. 32 (Suppl.), 490–495 (2002).

    Article  CAS  PubMed  Google Scholar 

  26. Jin, W. et al. The contributions of sex, genotype and age to transcriptional variance in Drosophila melanogaster. Nat. Genet. 29, 389–395 (2001).

    Article  CAS  PubMed  Google Scholar 

  27. Wolfinger, R.D. et al. Assessing gene significance from cDNA microarray expression data via mixed models. J. Comput. Biol. 8, 625–637 (2001).

    Article  CAS  PubMed  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

  1. Department of Genetics, North Carolina State University, Raleigh, 27695, North Carolina, USA

    Gisele Passador-Gurgel, Priscilla Hunt & Greg Gibson

  2. Department of Statistics, National Tsing Hua University, Hsinchu, 30013, Taiwan

    Wen-Ping Hsieh

  3. Metabolomics and Proteomics Laboratory, North Carolina State University, Raleigh, 27695, North Carolina, USA

    Nigel Deighton

Authors
  1. Gisele Passador-Gurgel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wen-Ping Hsieh
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Priscilla Hunt
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nigel Deighton
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Greg Gibson
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

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.

Corresponding author

Correspondence to Greg Gibson.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

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)

Supplementary Methods (PDF 187 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng1944

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing