17. Storey JD, Tibshirani R (2003) Statistical significance for genomewide studies. Proc Natl Acad Sci USA 100: 9440–9445. 18. Grewal SS (2009) Insulin/Tor signaling in growth and homeostasis: A view from the fly world. Int J Biochem Cell Biol 41: 1006–1010. 19. Wu Q, Brown MR (2006) Signaling and function of insulin-like peptides in insects. Annu Rev Entomol 51: 1–24. 20. Radimerski T, Montagne J, Rintelen F, Stocker H, van der Kaay J, et al. (2002) dS6K-regulated cell growth is dPKB/dPI(3)K-independent, but requires dPDK1. Nat Cell Biol 4: 251–255. 21. Rintelen F, Stocker H, Thomas G, Hafen E (2001) PDK1 regulates growth through Akt1 and S6k in Drosophila. Proc Natl Acad Sci USA 98: 15020–15025. 22. Junger MA, Rintelen F, Stocker H, Wasserman JD, Vegh M, et al. (2003) The Drosophila forkhead transcription factor foxo mediates the reduction in cell number associated with reduced insulin signaling. J Biol 2: 2–17. 23. Puig O, Marr MT, Ruhf ML, Tjian R (2003) Control of cell number by Drosophila foxo: Downstream and feedback regulation of the insulin receptor pathway. Genes Dev 17: 2006–2020. 24. Puig O, Tjian R (2005) Transcriptional feedback control of insulin receptor by dfoxo/foxo1. Genes Dev 19: 2435–2446. 25. Williams KD, Busto M, Suster ML, So AKC, Ben-Shahar Y, et al. (2006) Natural variation in Drosophila melanogaster diapause due to the insulin-regulated PI3-kinase. Proc Natl Acad Sci USA 103: 15911–15915. 26. Gibson G, Dworkin I (2004) Uncovering cryptic genetic variation. Nat Rev Genet 5: 681–690. 27. Mackay TF (2001) Quantitative trait loci in Drosophila. Nat Rev Genet 2: 11–20. 28. Buch S, Melcher C, Bauer M, Katzenberger J, Pankratz MJ (2008) Opposing effects of dietary protein and sugar regulate a transcriptional target of Drosophila insulin-like peptide signaling. Cell Metab 7: 321–332. 29. Gershman B, Puig O, Hang L, Peitzsch RM, Tatar M, et al. (2007) High- resolution dynamics of the transcriptional response to nutrition in Drosophila: A key role for dfoxo. Physiol Genomics 29: 24–34. 30. Guertin DA, Guntur KVP, Bell GW, Thoreen CC, Sabatini DM (2006) Functional genomics identifies Tor-regulated genes that control growth and division. Curr Biol 16: 958–970. 31. Engel JE, Xie XJ, Sokolowski MB, Wu CF (2000) A cGMP-dependent protein kinase gene, foraging, modifies habituation-like response decrement of the giant fiber escape circuit in Drosophila. Learn Mem 7: 341–352. 32. Mery F, Belay AT, Sokolowski MB, Kawecki TJ (2006) Antagonistic effects of natural polymorphism at the foraging locus on short-term learning and long-term memory. J Neurogenet 20: 177–177. 33. Kaun KR, Hendel T, Gerber B, Sokolowski MB (2007) Natural variation in Drosophila larval reward learning and memory due to a cGMP-dependent protein kinase. Learn Mem 14: 342–349. 34. Mery F, Belay AT, So AK, Sokolowski MB, Kawecki TJ (2007) Natural polymorphism affecting learning and memory in Drosophila. Proc Natl Acad Sci USA 104: 13051–13055. 35. Kaun KR, Riedl CAL, Chakaborty-Chatterjee M, Belay AT, Douglas SJ, et al. (2008) Natural variation in plasticity of glucose homeostasis and food intake. J Exp Biol 211: 3160–3166. 36. Fitzpatrick MJ, Sokolowski MB (2004) In search of food: Exploring the evolutionary link between cGMP-dependent protein kinase (PKG) and behaviour. Integr Comp Biol 44: 28–36. 37. You YJ, Kim J, Raizen DM, Avery L (2008) Insulin, cGMP, and TGF-beta signals regulate food intake and quiescence in C. elegans: A model for satiety. Cell Metab 7: 249–257. 38. Gray JM (2004) Oxygen sensation and social feeding mediated by a C. elegans guanylate cyclase homologue. Nature 430: 317–322. 39. Ben-Shahar Y, Leung HT, Pak WL, Sokolowski MB, Robinson GE (2003) cGMP-dependent changes in phototaxis: A possible role for the foraging gene in honey bee division of labor. J Exp Biol 206: 2507–2515. 40. Ingram KK, Oefner P, Gordon DM (2005) Task-specific expression of the foraging gene in harvester ants. Mol Ecol 14: 813–818. 41. Lucas C, Sokolowski MB (2009) Molecular basis for changes in behavioral state in ant social behaviors. Proc Natl Acad Sci USA 106: 6351–6356. 42. Lasko P, Sonenberg N (2007) Coordinated transcriptional and translational control in metabolic homeostasis in flies. Genes Dev 21: 235–237. 43. Ceddia RB, Bikopoulos GJ, Hilliker AJ, Sweeney G (2003) Insulin stimulates glucose metabolism via the pentose phosphate pathway in Drosophila Kc cells. FEBS Letters 555: 307–310. 44. Teleman AA, Chen YW, Cohen SM (2005) Drosophila melted modulates foxo and Tor activity. Dev Cell 9: 271–281. 45. Brogiolo W, Stocker H, Ikeya T, Rintelen F, Fernandez R, et al. (2001) An evolutionarily conserved function of the Drosophila insulin receptor and insulin- like peptides in growth control. Curr Biol 11: 213–221. 46. Bohni R, Riesgo-Escovar J, Oldham S, Brogiolo W, Stocker H, et al. (1999) Autonomous control of cell and organ size by chico, a Drosophila homolog of vertebrate IRS1-4. Cell 97: 865–875. 47. Britton JS, Lockwood WK, Li L, Cohen SM, Edgar BA (2002) Drosophila’s insulin/PI3-Kinase pathway coordinates cellular metabolism with nutritional conditions. Dev Cell 2: 239–249. 48. Kramer JM, Davidge JT, Lockyer JM, Staveley BE (2003) Expression of Drosophila foxo regulates growth and can phenocopy starvation. BMC Dev Biol 3: 1–14. foraging and Plasticity 49. Hwangbo DS, Gershman B, Tu MP, Palmer M, Tatar M (2004) Drosophila dfoxo controls lifespan and regulates insulin signalling in brain and fat body. Nature 429: 562–566. 50. Cohen P, Alessi DR, Cross DA (1997) PDK1, one of the missing links in insulin signal transduction? FEBS Letters 410: 3–10. 51. Nayar JK, Vanhande E (1971) Fuel for sustained mosquito flight. J Insect Physiol 17: 471–5. 52. Rowley WA (1970) Interval flights and glycogen utilization by mosquito Culex tarsalis. J Insect Physiol 16: 1839–&. 53. Wigglesworth VB (1949) The utilization of reserve substances in Drosophila during flight. J Exp Biol 26: 150–163. 54. Gade G, Auerswald L (2003) Mode of action of neuropeptides from the adipokinetic hormone family. Gen Comp Endocrinol 132: 10. 55. Graves JL, Toolson EC, Jeong C, Vu LN, Rose MR (1992) Desiccation, flight, glycogen, and postponed senescence in Drosophila melanogaster. Physiol Zool 65: 268–286. 56. Gibbs AG, Chippindale AK, Rose MR (1997) Physiological mechanisms of evolved desiccation resistance in Drosophila melanogaster. J Exp Biol 200: 1821–1832. 57. Hoffmann AA, Parsons PA (1989) Selection for increased desiccation resistance in Drosophila melanogaster: Additive genetic control and correlated responses for other stresses. Genetics 122: 837. 58. Hoffmann AA, Harshman LG (1999) Desiccation and starvation resistance in Drosophila: Patterns of variation at the species, population and intrapopulation levels. Heredity 83(Pt 6): 637. 59. Ballard JWO, Melvin RG, Simpson SJ (2008) Starvation resistance is positively correlated with body lipid proportion in five wild caught drosophila simulans populations. J Insect Physiol 54: 1371–1376. 60. Zhao Z, Zera AJ (2002) Differential lipid biosynthesis underlies a tradeoff between reproduction and flight capability in a wing-polymorphic cricket. Proc Natl Acad Sci USA 99: 16829–16834. 61. Zera AJ, Zhao Z (2003) Morph-dependent fatty acid oxidation in a wing- polymorphic cricket: implications for the trade-off between dispersal and reproduction. J Insect Physiol 49: 933–943. 62. Houle D (1991) Genetic covariance of fitness correlates: What genetic correlations are made of and why it matters. Evolution 45: 630–648. 63. Ota KT, Pierre VJ, Ploski JE, Queen K, Schafe GE (2008) The NO-cGMP- PKG signaling pathway regulates synaptic plasticity and fear memory consolidation in the lateral amygdala via activation of ERK/MAP Kinase. Learn Mem 15: 792–805. 64. Feil R, Hofmann F, Kleppisch T (2005) Function of cGMP-dependent protein kinases in the nervous system. Rev Neurosci 16: 23–41. 65. Liu S, Rao Y, Daw N (2003) Roles of Protein Kinase A and Protein Kinase G in synaptic plasticity in the visual cortex. Cereb Cortex 13: 864–869. 66. Wang X, Robinson P (1997) Cyclic GMP-dependent protein kinase and cellular signaling in the nervous system. J Neurochem 68: 443–456. 67. Dostmann WR, Tegge W, Frank R, Nickl CK, Taylor MS, et al. (2002) Exploring the mechanisms of vascular smooth muscle tone with highly specific, membrane-permeable inhibitors of cyclic GMP-dependent Protein Kinase I- alpha. Pharmacol Ther 93: 203–215. 68. Stuart JM, Segal E, Koller D, Kim SK (2003) A gene-coexpression network for global discovery of conserved genetic modules. Science 302: 249–255. 69. Engel JE, Wu CF (1996) Altered habituation of an identified escape circuit in Drosophila memory mutants. J Neurosci 16: 3486–3499. 70. Engel JE, Wu CF (1998) Genetic dissection of functional contributions of specific potassium channel subunits in habituation of an escape circuit in Drosophila. J Neurosci 18: 2254–2267. 71. Renger JJ, Yao WD, Sokolowski MB, Wu CF (1999) Neuronal polymorphism among natural alleles of a cGMP-dependent kinase gene, foraging, in drosophila. J Neurosci 19: RC28. 72. Dawson-Scully K, Armstrong GA, Kent C, Robertson RM, Sokolowski MB (2007) Natural variation in the thermotolerance of neural function and behavior due to a cGMP-dependent protein kinase. PLoS ONE 2: e773. doi:10.1371/ journal.pone.0000773. 73. Greenspan RJ (2001) The flexible genome. Nature Rev Genet 2: 383–387. 74. Featherstone DE, Broadie K (2002) Wrestling with pleiotropy: genomic and topological analysis of the yeast gene expression network. BioEssays 24: 267–274. 75. van Swinderen B, Greenspan RJ (2005) Flexibility in a gene network affecting a simple behavior in Drosophila melanogaster. Genetics 169: 2151–2163. 76. Promislow DE (2004) Protein networks, pleiotropy and the evolution of senescence. Proc Biol Sci 271: 1225–1234. 77. Benfey PN, Mitchell-Olds T (2008) From genotype to phenotype: systems biology meets natural variation. Science 320: 495–497. 78. Greenspan RJ (1997) A kinder, gentler genetic analysis of behavior: Dissection gives way to modulation. Curr Opin Neurobiol 7: 805–811. 79. Fitzpatrick MJ, Feder E, Rowe L, Sokolowski MB (2007) Maintaining a behaviour polymorphism by frequency-dependent selection on a single gene. Nature 447: 210–212. 80. Toma DP, White KP, Hirsch J, Greenspan RJ (2002) Identification of genes involved in Drosophila melanogaster geotaxis, a complex behavioral trait. Nat Genet 31: 349–353. PLoS Genetics | www.plosgenetics.org 12 August 2009 | Volume 5 | Issue 8 | e1000609