Degeneracy and Flexibility in Gene Networks

1. Degeneracy and Flexibility in Gene Networks Ralph J. Greenspan The Neurosciences Institute San Diego, CA

2. The Pathway Paradigm

4. Is it so neat and tidy?

8. mRNAs Higher in hi5 (199/8449) Gene expression swallow RNA binding protein Signal transduction nemo serine/threonine protein kinase Cytoskeleton & protein localization Pendulin nuclear importin a2-subunit zipper cytoplasmic myosin II heavy chain Klp67A kinesin-like protein Chaperones Hsp90 Hsp27 Hsp70 Hsp22 Hsp60

9. mRNAs Higher in lo (52/8449) Gene expression prospero homeodomain protein Circadian rhythms Pigment-dispersing factor neuropeptide cryptochrome photoreceptor protein Axon guidance abLIM actin-binding protein Immune system Attacin-A immune defense protein croquemort macrophage receptor

10. Importin-a (Pendulin) Pigment dispersing Factor (Pdf) cryptochrome (cry)

11. A’’ A’ A B’’ B’ B N’ N’’ N Genes Cells Phenotype

12. A syntaxin network

13. temperature-sensitive syntaxin (Syx1A) mutant % standing time 25oC 38oC

14. Isolation of syx suppressors syx + % standing syxSup + + time at 38oC van Swinderen and Greenspan (2005)

15. syx Suppressors Gene expression ETS domain zinc finger C2H2 NLS motif Srp54 (splicing factor) ATP-dependent DNA helicase S12 (ribosomal protein) Cytoskeleton troponin-C superfamily Actin 42A Chaperone kismet Metabolism pyruvate dehydrog. kinase Gdp-mannose \dehydratase Miscellaneous Cecropin-like A bunch of genes that don’t make sense 5 others unknown van Swinderen and Greenspan (2005)

16. observed expected Sup1Sup2 + + Sup1Sup2 + + Interaction between syx suppressors % standing time at 38oC van Swinderen and Greenspan (2005)

17. observed expected Sup1Sup2 + + Sup1Sup2 + + and in the presence of the syx- mutation syx + % standing syx + time at 38oC van Swinderen and Greenspan (2005)

18. syx + matrix 1 positive interaction negative interaction van Swinderen and Greenspan (2005)

19. syx- matrix 1 previous interaction missing interaction reversed sign van Swinderen and Greenspan (2005)

20. syx- matrix 1 previous interaction missing interaction reversed sign new interaction van Swinderen and Greenspan (2005)

21. syx+ matrix 2 positive interaction negative interaction

22. syx-matrix 2 previous interaction missing interaction reversed sign

23. syx-matrix 2 previous interaction missing interaction reversed sign new interaction

25. Gene networks appear to be responsive to changes (even mild changes) anywhere in the system.

27. Can you affect any phenotype from anywhere in the genome?

28. “Matrix” Experiment • 8 loci • range of functions and phenotypes • all expressed in the nervous system • place on common genetic background • test all pairwise combinations for 8 • different behaviors

29. Pendulin importin-a

30. Cysteine-string-protein synaptic transmission

31. Itp-r83A inositol-1,4,5-triphosphate receptor

32. methuselah G-coupled receptor

33. TBP-related factor TATA-box binding protein

34. nalyot/Adf1 Adf1 Adf1 Pol II transcription factor

35. Nemo Nemo Serine/threonine kinase

36. cnk Ras pathway modifier

37. Circadian rhythms (τ)

38. Sleep

39. Locomotor activity

40. Phototaxis

41. Geotaxis

42. Falling over % fainted time 25oC 38oC

43. ♀ Copulation Latency

44. ♀Copulation Duration

45. Large phenotypic effect nal Csp mth Trf Itp Pen cnk Nemo Cl Cd Cd Cd G τ F F F F F nal G G Csp F Cl τ Cl Cd mth τ G F F Trf F Itp Cl F Pen F Nemo cnk

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