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Design Principles in Biology: Evolutionary Insights and Molecular Networks

This presentation explores the fundamental design principles shaped by evolution and natural selection within biological systems. It discusses how specific molecular networks are optimized for effectiveness under varying conditions, highlighting principles in gene expression, metabolic networks, signal transduction, and development. By examining alternative designs and regulatory mechanisms, we aim to characterize network behavior and assess their biological functionality. Understanding these principles enriches our knowledge of how biology operates, connecting molecular determinants to functional outcomes.

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Design Principles in Biology: Evolutionary Insights and Molecular Networks

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  1. DesignPrinciples in Biology: a consequence of evolution and natural selection Rui Alves University of Lleida ralves@cmb.udl.es

  2. Climbingdownmount improbable • Overtime, edgedstoneswould accumulateontheslope. • Smooth, round, stones accumulate at the bottom. DesignPrinciples: - Smooth, roundishrocks roll downthemountain. - Edged, flat, rocksdon’t.

  3. Design principles in molecular biology • Similarly, if a topology or set of parameters can be shown to create a molecular network that functionally outperforms all other possible alternatives in a given set of conditions, one can talk about a design principle for the system under those conditions. [sensu engineering]

  4. Index of talk • How to identify design principles in molecular networks • Design principles in: • Gene expression • Metabolic networks • Signal transduction • Development • Design principles, what are they good for? • Summary

  5. First step, define the alternatives Regulator Regulator _ + Gene Gene X0 X1 X2 X3 X0 X1 X2 X3

  6. First step, define the alternatives X3 X0 X1 X2 X3 How strong should the feedback be? t

  7. Then, create models for each alternative Regulator Regulator _ + Gene Gene

  8. Then, create models for each alternative X0 X1 X2 X3 X0 X1 X2 X3

  9. Characterization of networkbehavior Biological functional effectiveness criteria for the network. Alternativedesigns … Comparison of behaviorbetweennetworks X1 … Xj … X1 … Xj … Mathematical models Enforce mathematical controls before analyzing model behavior

  10. Index of talk • How to identify design principles in molecular networks • Design principles in: • Gene expression • Metabolic networks • Signal transduction • Development • Design principles, what are they good for? • Summary

  11. The demand theory for gene expression Regulator Regulator _ • Are there situations where positive regulation of gene expression outperforms negative regulation of gene expression and vice versa? + Gene Gene

  12. Regulating gene expression has principles Regulator Regulator _ • Positive regulator: • More effective when gene product in demand for large fraction of life cycle. • Less noise sensitive if signal is low. • Negative regulator: • More effective when gene product in demand for small fraction of life cycle. • Less noise sensitive if signal is high. + Gene Gene Genetics 149:1665; PNAS 103:3999; PNAS 104:7151;Nature405: 590

  13. Glycogen Trehalose Regulating gene expression has principles

  14. Design principles in development

  15. Design principles in development

  16. Index of talk • How to identify design principles • Design principles in: • Gene expression • Metabolic networks • Signal transduction • Development • Design principles, what are they good for? • Summary

  17. Negative overall feedback is a design principle in metabolic biosynthesis • Negative overall feedback: • More effective in coupling production to demand. • More robust to fluctuations. X0 X1 X2 X3 Bioinformatics 16:786; Biophysical J. 79:2290

  18. Index of talk • How to identify design principles • Design principles in: • Gene expression • Metabolic networks • Signal transduction • Development • Design principles, what are they good for? • Summary

  19. Bifunctional sensors can be a design principle in signal transduction Signal Sensor Sensor Efector Deactivator Efector Effect • Bifunctional sensor: • Performs best against cross talk • Independent deactivator: • Better integrator of signals Mol. Microbiol. 48:25; Mol. Microbiol. 68: 1196

  20. Index of talk • How to identify design principles • Design principles in: • Gene expression • Metabolic networks • Signal transduction • Development • Design principles, what are they good for? • Summary

  21. Design principles in development Regulator Regulator _ Signal Highdemand, lowsignal + Signal _ Gene Gene + Highdemand, highsignal Lowdemand, lowsignal Lowdemand, highsignal Genetics 149:1665; PNAS 103:3999; PNAS 104:7151;Nature 405: 590

  22. Index of talk • How to identify design principles • Design principles in: • Gene expression • Metabolic networks • Signal transduction • Development • Design principles, what are they good for? • Summary

  23. Biological design principles are good to understand why biology works as it does • Biological design principles may connect molecular determinants to functional effectiveness. Expression of important genes Heat shock Growthrate time time BMC Bioinformatics 7:184

  24. Underlying assumption • Evolution of molecular networks can be treated as modules. • Work in the group of Uri Alon suggests that • networks evolving to meet simultaneous goals evolve in a modular fashion • Networks evolving to meet a single goal evolve globally • Modularity seems like a reasonable first assumption PNAS 102:13773; PLOS CompBiol 4:e1000206;BMC Evolbiol7: 169

  25. The good news about function • Sometimes, you get stuff for free!!! • For example: • networks that are responsive to signals, just because they are responsive may have inbuilt buffering of noise. • Functions that are associated with marginally stable proteins are favored because due to the large dimensions of sequence space most randomly selected sequences have a structure that is marginally stable. PNAS 100:14463; PNAS 103:6435; Proteins 46:105

  26. How can biological design principles be applied? • Design of molecular circuits with specific behaviors!! Bistablesystems Unstablesystems StableSystems Oscilations Cell 113: 597; PLoSComputBiol. 5:e1000319; PNAS 106: 6435

  27. Index of talk • How to identify design principles • Design principles in: • Gene expression • Metabolic networks • Signal transduction • Development • Design principles, what are they good for? • Summary

  28. Summary • Design principles can be found in molecular networks. • Such principles can sometimes be connected to selection for function effectiveness. • Even in the absence of such a connection, if they are valid they can be used to build biological circuits with specific behaviors.

  29. Acknowledgments Programa Ramon y CajalMCyT MCyT FCT NIH Mike Savageau Albert Sorribas Armindo Salvador Oleg Igoshin

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