1. Ohnologs and Regulatory Networks Robbie Sedgewick Group Meeting March 2, 2006

2. Ohnologs: paralogs that arose through polyploidization ● Ohnologs taken from YGOB (Byrne & Wolfe 2005) ● 554 Ohnolog pairs ● 1108/6540 = 17% of yeast genome is an ohnolog ● Relatively complete dataset. ● Sparse graph

3. Regulatory Network ● Harbison et al 2004. ● Used CHIP to identify binding locations for 203 TFs ● Of those, 102 TF’s had enough hits to determine TF binding sites (motifs) computationally with constraints on binding strength and (optionally) conservation. ● Noisy. ● Not complete.

4. Basic facts about the regulatory data. p < 0.001P < 0.005 No conservation “Loose” 9778 regulations Conserved in 2 yeasts Conserved in 3 yeasts “Strict” 3328 regulations

5. Duplicated transcription factors * Number of Ohnologs expected to be TFs 972*102/6540 =15 Ohnologs obs (exp) Paralogs obs (exp) 102 TFs Count37 (15) * 51 (40) Pairs14 + 27 203 TFs Count68 (30)110 (80) Pairs2681 + In some cases, only one member of a pair is considered a TF in Harbison et al data.

6. For more ohnolog and paralog stats with correlation coefficients: http://goby.compbio.cs.cmu.edu/DurandWiki/index. php/Ohnolog_and_paralog_pairs_that_are_transcri ption_factors

7. Combining ohnology and regulation g1 is significantly similar to g3 g1 regulates g2 g1 g2 g3 g4g5 g4 is significantly similar to g5 and regulates g5

8. Compare with randomized graphs Compare with paralogs Null hypotheses

9. Paralogs ● Use sequence similarity to determine Paralogy. ● Eval cutoff of 10 -10. (soon to use NC) ● 8572 paralogous pairs ● Dense (compared to ohnologs) ● Error prone

10. Randomization method ● Method due to George and Robbie ● Take two networks and scramble the name mapping between them. ● Results in random combination of graphs that preserves network properties (e.g., node degree) of both component graphs.

11. Randomization method (name lookup) (scrambled lookup table)

12. Results How often is a gene regulated by both members of an ohnolog pair? How often are both members of an ohnolog pair regulated by the same TF? Geometric motifs

13. …both members of an ohnolog pair? …only one member of an ohnolog pair? How many genes are regulated by … For comparison, how many ohnolog pairs regulate at least one common target? Note: a target may be counted more than once if regulated by more than one ohnolog pair.

14. Genes regulated by only one member of an ohnolog pair Strict Genes regulated by both members of an ohnolog pair Ohnolog pairs that regulate at least one common target TrianglesNumRandavp-val Ohnologs10912.10 -4 Paralogs2572510 -4 NumRandavp-val Ohnologs989118010 -4 Paralogs250230809.5x10 -3 PairsNumRandavp-val Ohnologs102.810 -4 Paralogs165.310 -4

15. Genes regulated by only one member of an ohnolog pair Loose Genes regulated by both members of an ohnolog pair Ohnolog pairs that regulate at least one common target

16. Results How often is a gene regulated by both members of an ohnolog pair? How often are both members of an ohnolog pair regulated by the same TF? Geometric motifs

17. …both members of an ohnolog pair? …only one member of an ohnolog pair? How often does a transcription factor regulate For comparison, how many ohnolog pairs have at least one regulator in common?

18. Strict Genes that regulate only one member of an ohnolog pair TFs that regulate both members of an ohnolog pair Ohnolog pairs have at least one regulator in common TrianglesNumRandavp-val Ohnologs388.210 -4 Paralogs2679010 -4 NumRandavp-val Ohnologs71677610 -4 Paralogs9994109000.11 PairsNumRandavp-val Ohnologs266.810 -4 Paralogs2098010 -4

19. Loose Genes that regulate only one member of an ohnolog pair TFs that regulate both members of an ohnolog pair Ohnolog pairs have at least one regulator in common

20. Results How often is a gene regulated by both members of an ohnolog pair? How often are both members of an ohnolog pair regulated by the same TF? Geometric motifs

21. Motifs and evolution We can understand complex motifs by considering what happens after a whole genome duplication. WGD Loss

22. Results: one pair Regulates Partner Regulate each other Strict NumRandavp-val Ohnologs40.526x10 -4 Paralogs81.02x10 -4 NumRandavp-val Ohnologs10.04 Paralogs10.0439

23. Results: one pair Regulates Partner Regulate each other Loose NumRandavp-val Ohnologs51.35.3x10 -3 Paralogs112.61x10 -4 NumRandavp-val Ohnologs10.065 Paralogs10.06150.0603

24. For pictures of these motifs ● http://www.cs.cmu.edu/~bobsedge/images/all-self- reg.pdf http://www.cs.cmu.edu/~bobsedge/images/all-self- reg.pdf ● http://www.cs.cmu.edu/~bobsedge/images/all-self- reg-loose.pdf http://www.cs.cmu.edu/~bobsedge/images/all-self- reg-loose.pdf

25. Motifs and evolution We can understand complex motifs by considering what happens after a whole genome duplication. WGD Loss

26. Results: Two pairs 0 loss 1 loss 2 loss Strict

27. Results: Two pairs 0 loss 1 loss 2 loss Loose

28. For a table with more complete motif stats: http://www.cs.cmu.edu/~bobsedge/images/tablemod.pdf

29. An example: Duplicated Iron Pathway? ● AFT1 and AFT2 are TFs that are also ohnologs and both regulate iron deprivation response pathways. ● 26 of the 60 genes regulated by AFT2 are ohnologs (strict). ● Maybe iron deprivation response pathway was duplicated in WGD? buffering? AFT1 and AFT2 motif: http://www.cs.cmu.edu/~bobsedge/images/AFT2_an d_friends2.pdf

30. Additional Sources of Data ● Gene Coexpression ● Synthetic Lethal interactions ● Protein-Protein interactions (Y2H) ● Domain information ● Genes that were ohnologs (singletons from YGOB)