Abstract
Determining the genetic architecture of complex traits is challenging because phenotypic variation arises from interactions between multiple, environmentally sensitive alleles. We quantified genome-wide transcript abundance and phenotypes for six ecologically relevant traits in D. melanogaster wild-derived inbred lines. We observed 10,096 genetically variable transcripts and high heritabilities for all organismal phenotypes. The transcriptome is highly genetically intercorrelated, forming 241 transcriptional modules. Modules are enriched for transcripts in common pathways, gene ontology categories, tissue-specific expression and transcription factor binding sites. The high degree of transcriptional connectivity allows us to infer genetic networks and the function of predicted genes from annotations of other genes in the network. Regressions of organismal phenotypes on transcript abundance implicate several hundred candidate genes that form modules of biologically meaningful correlated transcripts affecting each phenotype. Overlapping transcripts in modules associated with different traits provide insight into the molecular basis of pleiotropy between complex traits.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Accession codes
References
Falconer, D.S. & Mackay, T.F.C. Introduction to Quantitative Genetics (Addison Wesley Longman, Harlow, Essex, UK, 1996).
Lynch, M. & Walsh, B. Genetics and Analysis of Quantitative Traits (Sinauer Associates, Sunderland, Massachusetts, 1998).
Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 44, 66–678 (2007).
Mackay, T.F.C. & Anholt, R.R.H. Of flies and man: Drosophila as a model for human complex traits. Annu. Rev. Genomics Hum. Genet. 7, 339–367 (2006).
Valdar, W. et al. Genetic and environmental effects on complex traits in mice. Genetics 174, 959–984 (2006).
Sieberts, S.K. & Schadt, E.E. Moving toward a system genetics view of disease. Mamm. Genome 18, 389–401 (2007).
Emilsson, V. et al. Genetics of gene expression and its effect on disease. Nature 452, 423–428 (2008).
Chen, Y. et al. Variations in DNA elucidate molecular networks that cause disease. Nature 452, 429–435 (2008).
Rollmann, S.M. et al. Pleiotropic fitness effects of the Tre1/Gr5a region in Drosophila. Nat. Genet. 38, 824–829 (2006).
Sambandan, D., Yamamoto, A., Fanara, J.J., Mackay, T.F.C. & Anholt, R. R. Dynamic genetic interactions determine odor-guided behavior in Drosophila melanogaster. Genetics 174, 1349–1363 (2006).
Storey, J.D. & Tibshirani, R. Statistical significance for genomewide studies. Proc. Natl. Acad. Sci. USA 100, 9440–9445 (2003).
Ellegren, H. & Parsch, J. The evolution of sex-biased genes and sex-biased gene expression. Nat. Rev. Genet. 8, 689–698 (2007).
Zhang, Y., Sturgill, D., Parisi, M., Kumar, S. & Oliver, B. Constraint and turnover in sex-biased gene expression in the genus Drosophila. Nature 450, 233–237 (2007).
Dennis, G. et al. DAVID: Database for Annotation, Visualization, and Integrated Discovery. Genome Biol. 4, 3 (2003).
Sturgill, D., Zhang, Y., Parisi, M. & Oliver, B. Demasculinization of X chromosomes in the Drosophila genus. Nature 450, 238–241 (2007).
Drosophila 12 Genomes Consortium. Evolution of genes and genomes on the Drosophila phylogeny. Nature 45, 203–218 (2007).
Mackay, T.F.C. et al. Genetics and genomics of Drosophila mating behavior. Proc. Natl. Acad. Sci. USA 102, 6622–6629 (2005).
Edwards, A.C., Rollmann, S.M., Morgan, T.J. & Mackay, T.F.C. Quantitative genomics of aggressive behavior in Drosophila melanogaster. PLoS Genet. 2, e154 (2006).
Jordan, K.W., Carbone, M.A., Yamamoto, A., Morgan, T.J. & Mackay, T.F.C. Quantitative genomics of locomotor behavior in Drosophila melanogaster. Genome Biol. 8, R172 (2007).
Morozova, T.V., Anholt, R.R.H. & Mackay, T.F.C. Phenotypic and transcriptional response to selection for alcohol sensitivity in Drosophila melanogaster. Genome Biol. 8, R231 (2007).
Chintapalli, V.R., Wang, J. & Dow, J.A.T. Using FlyAtlas to identify better Drosophila models of human disease. Nat. Genet. 39, 715–720 (2007).
Robertson, L.K., Bowling, D.B., Mahaffey, J.P., Imiolczyk, B. & Mahaffey, J.W. An interactive network of zinc-finger proteins contributes to regionalization of the Drosophila embryo and establishes the domains of HOM-C protein function. Development 131, 2781–2789 (2004).
Wilson, R.J., Goodman, J.L. & Strelets, V.B. FlyBase: integration and improvements to query tools. Nucleic Acids Res. 36, D588–D593 (2008).
Robertson, A. in Heritage From Mendel (ed. Brink, A.) 265–280 (Univ. Wisconsin, Madison, Wisconsin, 1967).
Passador-Gurgel, G., Hsieh, W.P., Hunt, P., Deighton, N. & Gibson, G. Quantitative trait transcripts for nicotine resistance in Drosophila melanogaster. Nat. Genet. 39, 264–268 (2007).
Yamamoto, A. et al. Neurogenetic networks for startle-induced locomotion in Drosophila melanogaster. Proc. Natl. Acad. Sci. USA 105, 12393–12398 (2008).
Lung, O., Kuo, L. & Wolfner, M.F. Drosophila males transfer antibacterial proteins from their accessory gland and ejaculatory duct to their mates. J. Insect Physiol. 47, 617–62 (2001).
Wolfner, M.F. “S.P.E.R.M.” (seminal proteins (are) essential reproductive modulators): the view from Drosophila. Soc. Reprod. Fertil. Suppl. 65, 183–199 (2007).
Date-Ito, A., Kasahara, K., Sawai, H. & Chigusa, S.I. Rapid evolution of the male-specific antibacterial protein andropin gene in Drosophila. J. Mol. Evol. 54, 665–670 (2002).
Wong, A., Turchin, M.C., Wolfner, M.F. & Aquadro, C.F. Evidence for positive selection on Drosophila melanogaster seminal fluid protease homologs. Mol. Biol. Evol. 25, 497–506 (2008).
Wigby, S. & Chapman, T. Sex peptide causes mating costs in female Drosophila melanogaster. Curr. Biol. 15, 316–321 (2005).
Kim, D.-H. et al. mTOR interacts with Raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 110, 163–175 (2002).
Kamada, Y. et al. Autophagy in yeast: a TOR-mediated response to nutrient starvation. Curr. Top. Microbiol. Immunol. 279, 73–84 (2004).
Jin, W. et al. The contributions of sex, genotype and age to transcriptional variance in Drosophila melanogaster. Nat. Genet. 29, 389–395 (2001).
Monks, S.A. et al. Genetic inheritance of gene expression in human cell lines. Am. J. Hum. Genet. 75, 1094–1105 (2004).
Morley, M. et al. Genetic analysis of genome-wide variation in human gene expression. Nature 430, 743–747 (2004).
Oleksiak, M.F., Churchill, G.A. & Crawford, D.L. Variation in gene expression within and among natural populations. Nat. Genet. 32, 261–266 (2002).
Schadt, E.E. et al. Genetics of gene expression surveyed in maize, mouse and man. Nature 422, 297–302 (2003).
Stranger, B.E. et al. Genome-wide associations of gene expression variation in humans. PLoS Genet. 1, e78 (2005).
Brem, R.B. & Kruglyak, L. The landscape of genetic complexity across 5,700 gene expression traits in yeast. Proc. Natl. Acad. Sci. USA 102, 1572–1577 (2005).
Chesler, E.J. et al. Complex trait analysis of gene expression uncovers polygenic and pleiotropic networks that modulate nervous system function. Nat. Genet. 37, 233–242 (2005).
Cheung, V.G. et al. Mapping determinants of human gene expression by regional and genome-wide association. Nature 437, 1365–1369 (2005).
Hubner, N. et al. Integrated transcriptional profiling and linkage analysis for identification of genes underlying disease. Nat. Genet. 37, 243–253 (2005).
Lemos, B., Ararope, L.O., Fontanillas, P. & Hartl, D.L. Dominance and the evolutionary accumulation of cis- and trans-effects on gene expression. Proc. Natl. Acad. Sci. USA 105, 14471–14476 (2008).
Knight, G.R. & Robertson, A. Fitness as a measureable character in Drosophila. Genetics 42, 524–530 (1957).
Hartl, D.L. & Jungen, H. Estimation of average fitness of populations of Drosophila melanogaster and the evolution of fitness in experimental populations. Evolution 33, 371–380 (1979).
Foronda, D. et al. Requirement of Abdominal-A and Abdominal-B in the developing genitalia of Drosophila breaks the posterior downregulation rule. Development 133, 117–127 (2005).
DeZazzo, J. et al. nalyot, a mutation of the Drosophila myb-related Adf1 transcription factor, disrupts synapse formation and olfactory memory. Neuron 27, 145–158 (2000).
Acknowledgements
This work was supported by grants from the National Institutes of Health (R01 GM 45146, R01 GM 076083, R01 AA016560 to T.F.C.M. and R01 GM 59469 to R.R.H.A.). The authors thank S. Heinsohn for technical assistance. This is a publication of the W. M. Keck Center for Behavioral Biology.
Author information
Authors and Affiliations
Contributions
T.F.C.M., J.F.A., E.A.S. and R.R.H.A. wrote the paper. R.F.L. constructed the Drosophila lines. M.A.C. obtained the gene expression data. K.W.J., M.M.M., S.M.R., L.H.D. and F.L. obtained the organismal phenotype data. J.F.A., E.A.S. and K.W.J. performed the statistical analyses.
Corresponding author
Supplementary information
Supplementary Table 1
Quantitative genetic analyses of variation for 14,480 expressed transcripts in 40 wild-derived inbred lines. Expression is measured as the median log2 intensity of PM transcripts in each probe set that do not contain SFPs. (XLS 5595 kb)
Supplementary Table 2
Over-representation of Gene Ontology Categories, KEGG Pathways and KOG Ontologies for two-fold male and female biased transcripts, transcripts with high (> 0.8) and low (< 0.2) broad sense heritabilities (H2), and transcripts with low (< 0.2) cross-sex genetic correlations (rMF). (XLS 134 kb)
Supplementary Table 3
Enrichment of transcription factor motifs in 5′ UTR sequences of genes in modules of correlated transcripts. (XLS 251 kb)
Supplementary Table 4
Quantitative genetics of organismal phenotypes for 40 wild-derived inbred lines. (PDF 157 kb)
Supplementary Table 5
Associations of SFPs with quantitative traits. (XLS 291 kb)
Supplementary Table 6
Transcripts and modules of correlated transcripts associated with each of six quantitative traits. (XLS 985 kb)
Supplementary Table 7
Effects of P[GT1] insertional mutations in candidate genes affecting resistance to starvation stress and chill coma recovery time. (XLS 96 kb)
Supplementary Table 8
Over-representation of Gene Ontology Categories, KEGG Pathways and Keywords for transcripts associated with quantitative trait phenotypes. (XLS 188 kb)
Rights and permissions
About this article
Cite this article
Ayroles, J., Carbone, M., Stone, E. et al. Systems genetics of complex traits in Drosophila melanogaster. Nat Genet 41, 299–307 (2009). https://doi.org/10.1038/ng.332
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/ng.332
This article is cited by
-
Modulation of the Drosophila transcriptome by developmental exposure to alcohol
BMC Genomics (2022)
-
Low dose rate γ-irradiation protects fruit fly chromosomes from double strand breaks and telomere fusions by reducing the esi-RNA biogenesis factor Loquacious
Communications Biology (2022)
-
Transcriptome profiling revealed potentially important roles of defensive gene expression in the divergence of insect biotypes: a case study with the cereal aphid Sitobion avenae
BMC Genomics (2020)
-
The strength and pattern of natural selection on gene expression in rice
Nature (2020)
-
Heritability of resistance-related gene expression traits and their correlation with body size of clam Meretrix petechialis
Journal of Oceanology and Limnology (2020)