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Finding the building blocks of RNA 3-D structure using graph analysis

Finding the building blocks of RNA 3-D structure using graph analysis. Romain Rivière AReNa – 28.03.2007. Interest in RNA modelling. Characterise RNA families Improve non- coding RNA identification in genomic data Determine the RNA players in regulatory networks

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Finding the building blocks of RNA 3-D structure using graph analysis

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  1. Finding the building blocks of RNA 3-D structure using graph analysis Romain Rivière AReNa– 28.03.2007

  2. Interest in RNA modelling • Characterise RNA families • Improve non-coding RNA identification in genomic data • Determine the RNA players in regulatory networks • Identifypotential RNA drugtargets

  3. Project Background: ribonomicsiscurentlystuckwith the secondary structure paradigm, whereaswewouldneedhighthroughputtertiary data Hypothesis: Finding the fundamental building blocks of RNA structures willreduce the complexity of RNA folding

  4. RNA 3-D Structure interactions

  5. From 3-D Structure to Graph :MC-Annotate YeasttRNA-Phecrystal structure (pdb 4TNA)

  6. Solution in 3 steps Enumerate all the motifs Regroup by similarity Find the building blocks

  7. Enumerating motifs : The backbonehelps !

  8. Enumerating motifs A motif is a set of connectednucleotidestogetherwiththeir interactions

  9. Enumerating motifs

  10. 344 motifs of size 4 in tRNA …

  11. Solution in 3 steps Enumerate all the motifs Regroup by similarity Find the building blocks

  12. Graph Isomorphism 1 2 4 2 1 2 = 5 3 3 Scan through all permutations to decide if two graphs are isomorphic ! 1 5 3 4 5 4 Matrixrepresentation of the graph : 2 1 0 1 0 0 1 1 0 1 1 0 0 1 0 1 0 0110 1 1 0 0 1 0 0 1 0 0 1 1 0 1 1 0 0 1 0 1 0 0110 1 1 0 0 1 0 0 1 0 1 1 1 0 1 1 0 0 1 0 0 1 1 1 0 0 0 1 0 1 0 0 = ≠

  13. ? ? ? ? ? ? ? ? Group motifs withisomorphism

  14. Canonical labelling 1 2 4 2 1 2 = 5 3 3 Take the minimum through all permutations of the matrixrepresentation 1 5 3 4 5 4 Matrixrepresentation of the graph : 2 1 0 1 0 0 1 1 0 1 1 0 0 1 0 1 0 0110 1 1 0 0 1 0 0 1 0 0 1 1 0 1 1 0 0 1 0 1 0 0110 1 1 0 0 1 0 0 1 0 1 1 1 0 1 1 0 0 1 0 0 1 1 1 0 0 0 1 0 1 0 0 = ≠

  15. 18 21 18 33 21 21 Group motifs with canonical labelling

  16. Solution in 3 steps Enumerate all the motifs Regroup by similarity Find the building blocks

  17. Occurrences of a motif in the 50S rRNA of H. marismortui

  18. The covering graph : a mappingbetween motifs and edges Type of motifs Edges 7 5 4 7 6 Find a small set of types of motifs thatcovers the mostedges 10 7 4 3 0 … …

  19. Building blocks of the 50S?(graphs of size 4) General graphs are not compact enough Not usable for modelling …

  20. 334 Building blocks of the 50S(cycles of sizes 3 to 6) …

  21. The colored Ribosome

  22. The colored 16S

  23. Covering for the PDB database

  24. Future works • Motif discovery • Biological relevance of block-functionrelationships? • RNA folding • Practicalusability?

  25. Acknowledgments • François Major • Sébastien Lemieux • Véronique Lisi • Karine St-Onge • Philippe Thibault • Patrick Gendron • Martin Larose • All otherlabmembers

  26. Thankyou…

  27. The Results Weapplied the method to the large ribosomal subunit Werestrict the graphs allowed for the base to cycles Wefound 334 cycles thatcovers 90% of the structure.

  28. Canonical labeling Canonical label of a graph : Take the minimum of the matrices over all the permutations Property : 2 graphs have the same canonical label if and only if they are isomorphic

  29. Second step : group motifs • Group together motifs which are identical • Donewith canonical labelling • Idea : associate a string to each graph suchthattwo graphs are associatedwith the same string if and only if they are identical (isomorphic). • Difficultproblemwellstudied • Potentiallyhighly computation time.

  30. The construction of a bipartite graph

  31. Conformationalspacetoo large 3^n . 10^n where n is the size of the structure 10^14 op/s world fastest computer

  32. Letter ‘A’ : GC base paire

  33. Letter ‘SarcinRiccin’

  34. Letter ‘GNRA’

  35. Letter ‘crossing’

  36. Letter ‘GNRA’ (2)

  37. Interests in RNA RNA is a very important medium in the transfer of genetic information Convey information throughits structure in addition to itssequence Example : miRNA

  38. miRNAPathway

  39. Structure of an miRNA Similarsecondary structure But, only one miRNAfunctional !

  40. RNA 3-D Structure ineractions • 3 main types of molecular interactions : • Phosphodiesterlink • Base pairing • Base stacking

  41. RNA 3-D Structure interactions : Backboneconnectivity

  42. RNA 3-D Structure interactions : Base pairing types

  43. RNA 3-D Structure interations : Base stacking types

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