Transcript robbie0306
Ohnologs and Regulatory Networks Robbie Sedgewick Group Meeting March 2, 2006 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 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. Basic facts about the regulatory data. p < 0.001 No conservation Conserved in 2 yeasts Conserved in 3 yeasts P < 0.005 “Loose” 9778 regulations “Strict” 3328 regulations Duplicated transcription factors Ohnologs obs (exp) Paralogs obs (exp) 102 TFs Count 37 (15)* 51 (40) Pairs 14+ 27 203 TFs Count 68 (30) 110 (80) Pairs 26 81 * Number of Ohnologs expected to be TFs 972*102/6540 =15 + In some cases, only one member of a pair is considered a TF in Harbison et al data. 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 Combining ohnology and regulation g1 is significantly similar to g3 g1 g1 regulates g2 g2 g3 g4 g5 g4 is significantly similar to g5 and regulates g5 Null hypotheses Compare with paralogs Compare with randomized graphs 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 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. Randomization method (name lookup) (scrambled lookup table) 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 How many genes are regulated by … …both members of an ohnolog pair? …only one member of an ohnolog pair? Note: a target may be counted more than once if regulated by more than one ohnolog pair. For comparison, how many ohnolog pairs regulate at least one common target? Strict Genes regulated by both members of an ohnolog pair Triangles Num Randav p-val Ohnologs 109 12. 10-4 Paralogs 257 25 10-4 Genes regulated by only one member of an ohnolog pair Num Randav p-val Ohnologs 989 1180 10-4 Paralogs 2502 3080 9.5x10-3 Ohnolog pairs that regulate at least one common target Pairs Num Randav p-val Ohnologs 10 2.8 10-4 Paralogs 16 5.3 10-4 Loose Genes regulated by both members of an ohnolog pair Triangles Num Rand Avg Pval Ohnologs 424 4.4 0 .0 0 0 1 Paralogs 8 58 19 0 .0 0 0 1 Genes regulated by only one member of an ohnolog pair Num Rand Avg Pval Ohnologs 30 9 8 3,9 40 0 .0 0 0 1 Paralogs 779 2 35,0 0 0 0 .0 0 0 1 Ohnolog pairs that regulate at least one common target Num Rand Avg Pval Pairs Ohnologs 13 0 .43 0 .0 0 0 1 Paralogs 24 2 0 .0 0 0 1 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 How often does a transcription factor regulate …both members of an ohnolog pair? …only one member of an ohnolog pair? For comparison, how many ohnolog pairs have at least one regulator in common? Strict TFs that regulate both members of an ohnolog pair Triangles Num Randav p-val Ohnologs 38 8.2 10-4 Paralogs 267 90 10-4 Genes that regulate only one member of an ohnolog pair Num Randav p-val Ohnologs 716 776 10-4 Paralogs 9994 10900 0.11 Ohnolog pairs have at least one regulator in common Pairs Num Randav p-val Ohnologs 26 6.8 10-4 Paralogs 209 80 10-4 Loose TFs that regulate both members of an ohnolog pair Triangles Num Rand Avg Pval Ohnologs 131 43 0 .0 0 0 1 Paralogs 1,20 7 602 0 .0 0 0 1 Genes that regulate only one member of an ohnolog pair Num Rand Avg Pval Ohnologs 1,774 1950 0.0001 Paralogs 30,240 31,700 0.1800 Ohnolog pairs have at least one regulator in common Num Rand Avg Pval Pairs Ohnologs 73 34 0 .0 0 0 1 Paralogs 78 3 479 0 .0 0 0 1 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 Motifs and evolution We can understand complex motifs by considering what happens after a whole genome duplication. WGD Loss Results: one pair Regulate each other Regulates Partner Num Rand Avg Pval Ohnologs 4 0 .34 0 .0 0 0 2 Paralogs 8 2.4 0 .0 143 Num Randav Num Rand Avg Pval Ohnologs 1 0 .0 0 24 0 .0 0 25 Paralogs 1 0 .0 0 46 0 .0 0 47 Num p-val Randav p-val 0.04 Ohnologs 4 0.52 6x10-4 Ohnologs 1 0.04 Paralogs 8 1.0 2x10-4 Paralogs 1 0.0439 Strict 0.0439 Results: one pair Regulate each other Regulates Partner Num Rand Avg Pval Ohnologs 5 0 .8 8 0 .0 0 12 Paralogs 11 6 .9 0 .16 0 0 Num Randav Num Rand Avg Pval Ohnologs 1 0 .0 0 38 0 .0 0 39 Paralogs 1 0 .0 0 6 3 0 .0 0 6 4 p-val Num Randav p-val Ohnologs 5 1.3 5.3x10-3 Ohnologs 1 0.065 0.065 Paralogs 11 2.6 1x10-4 Paralogs 1 0.0615 0.0603 Loose For pictures of these motifs ● ● http://www.cs.cmu.edu/~bobsedge/images/all-selfreg.pdf http://www.cs.cmu.edu/~bobsedge/images/all-selfreg-loose.pdf Motifs and evolution We can understand complex motifs by considering what happens after a whole genome duplication. WGD Loss Results: Two pairs 1 loss 0 loss Com plet e Num Rand Avg Pval Ohnologs 0 0 1.0 0 0 0 Paralogs 20 0 .0 2 0 .0 0 0 1 Ns Num Rand Avg Pval Ohnologs 3 0 .0 1 0 .0 0 0 1 Paralogs 73 0 .27 0 .0 0 0 1 2 loss Box+ t ri Num Rand Avg Pval Ohnologs 43 3.6 0.0001 Paralogs 73 0.27 0.0001 Strict Results: Two pairs 1 loss 0 loss Com plet e Num Rand Avg Pval Ohnologs 5 0 .0 0 51 0 .0 0 0 1 Paralogs 75 0 .21 0 .0 0 0 1 Ns Num Rand Avg Pval Ohnologs 17 0 .0 9 0 .0 0 0 1 Paralogs 26 7 4.2 0 .0 0 0 1 2 loss Box+ t ri Num Rand Avg Pval Ohnologs 175 22 0 .0 0 0 1 Paralogs 9 51 138 0 .0 0 0 1 Loose For a table with more complete motif stats: http://www.cs.cmu.edu/~bobsedge/images/tablemod.pdf 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 Additional Sources of Data ● ● ● ● ● Gene Coexpression Synthetic Lethal interactions Protein-Protein interactions (Y2H) Domain information Genes that were ohnologs (singletons from YGOB)