1. 1. Inferring orthologous gene regulatory networks using interspecies data fusion 2015/8/10 ISMB/ECCB 2015@ @antiplastics
2. 2. 2011
3. 3. 1. Introduction
4. 4. Gene Regulatory NetworkGRNs http://www.nature.com/ncomms/journal/ v4/n5/g_tab/ncomms2693_F2.html DNA Togo picture gallery by DBCLS is licensed under a Creative Commons Attribution 2.1 Japan license (c) Gene X Gene Y Gene Z X Y Z
5. 5. JI&NL Joint inferenceJI Network leveragingNL GRNs2Fig.1 GRNs GRNs GRNs GRNs GRNs GRNs DNA Hyper network
6. 6. JI&NL Clark and Kalita, 2014 Towfic et al., 2009 1:1 : &
7. 7. Step.1 : GRNs CSI tntn-1 t2t1 X(1) X(2) X(n-1) X(n) tntn-1 t2t1 X(1) X(2) X(n-1) X(n) tntn-1 t2t1 X(1) X(2) X(n-1) X(n) time tntn-1 t2t1 Organism 1 X(1) X(2) X(n-1) X(n) g1 g2 gn-1 gn
8. 8. time tntn-1 t2t1 Organism d X(1) X(2) X(n-1) X(n) g1 g2 gn-1 gn time tntn-1 t2t1 Organism 2 X(1) X(2) X(n-1) X(n) g1 g2 gn-1 gn tntn-1 t2t1 X(1) X(2) X(n-1) X(n) time tntn-1 t2t1 Organism 1 X(1) X(2) X(n-1) X(n) g1 g2 gn-1 gn Step.2 : Step.1
9. 9. time tntn-1 t2t1 Organism d X(1) X(2) X(n-1) X(n) g1 g2 gn-1 gn time tntn-1 t2t1 Organism 2 X(1) X(2) X(n-1) X(n) g1 g2 gn-1 gn tntn-1 t2t1 X(1) X(2) X(n-1) X(n) time tntn-1 t2t1 Organism 1 X(1) X(2) X(n-1) X(n) g1 g2 gn-1 gn Step.3 : GRNs
10. 10. 2. Leveraging orthologous networks via Bayesian inference
11. 11. X = X(1) , X(2) ,..., X(d) { } Xd GRNsgd g(1) ,g(2) ,...,g(d) { } gNE l g(i) = {N(i) , E(i) ,l(i) }
12. 12. Framework1JI X g d g Hyper Network Data Hyper Parameter Graph Model Parameter P(g(1) ,...,g(d) ,g*| X,,) P(g(1) ,...,g(d) ,g*| ) P(X( j) | g( j) ,( j) ) j=1 d g* = {N*, E*,l*} Hyper Network P(X( j) | g( j) ,( j) ) = L(g( j) |( j) ) Zdata (( j) ) g(j)
13. 13. Framework1JI P(g(1) ,...,g(d) ,g*| ) = exp((g(1) ,...,g(d) ,g*)) ZGK () MCMC Hypernetwork 0g(d)GRNs GRNs (g(1) ,...,g(d) ,g*) = (g( j) ,g*) j=1 d
14. 14. Framework1JI (g(1) ,...,g(d) ,g*) =0 K(g(1) ,g*) j=1 d Oates, 2014, Penfold et al, 2012, Werhli and Husmeier, 2008 (g( j) ,g*) = d(g( j) ,g*) 3 0 = max g( j ) ,...,g* { K(g( j) ,g*) j=1 d }
15. 15. Framework2NL Framework1Hyper network (g(1) ,...,g(d) ) =0 K(g(i) ,g( j) ) i=j+1 d j=1 d P(g(1) ,...,g(d) | X,,) P(g(1) ,...,g(d) | ) P(X( j) | g( j) ,( j) ) j=1 d X g d Data Hyper Parameter Graph Model Parameter
16. 16. : Data1 Data2 Data3 Data4 CCAFisher SVMK-meansPLS SVRetc Data 1 Data 2 Data 3 Data 4 Data 1 Data 2 Data 3 Data 4 Data1 Data4 Data3 Data2 PC1 PC2 PC3 PCA
17. 17. : 1: (x1),(x2 ) = K(x1, x2 ) x1 x2 (x1) (x2)
18. 18. : 2: ATAGGA ACGGT AGGTG GTCAC
19. 19. :
20. 20. Shortest path graph kernel Kshortest path g 1( ) ,g 2( ) ( )= kwalk 1 e(1) ,e(2) ( ) e(2) Esp 2( ) e(1) Esp 1( ) g 1( ) g 2( ) gene1 gene2 gene3 gene4 gene5 gene1 gene2 gene3 gene4 gene5 : gene2gene5 E : e : kwalk : Borgwardt and Kriegel, 2005 3 gene3 1
21. 21. Graphlet kernel Kg g 1( ) ,g 2( ) ( )= fg 1( ) T fg 2( ) = g 1( ) g 2( ) gene1 gene2 gene3 gene4 gene5 gene1 gene2 gene3 gene4 gene5 : gene3,4,5 3 Dg(1) = fg(1) Ng(1) Kg g 1( ) ,g 2( ) ( )= Dg 1( ) T Dg 2( ) gene3 fg 1( ) T fg 2( ) = (0,1,0,0)(0,1,0,0) =1 1
22. 22. Weisfeiler-Lehman (WL) kernel K b( ) WL g 1( ) ,g 2( ) ( )= k gi 1( ) ,gi 2( ) ( )i=0 h WL g 1( ) g 2( ) 1 2 3 4 5 1 2 3 4 5 : h=0WL 3 k g0 1( ) ,g0 2( ) ( )= (g0 1( ) )(g0 2( ) ) = (1,1,2,1,1) (1,1,1,1,1) =1+1+ 2 +1+1 = 5 5
23. 23. Weisfeiler-Lehman (WL) kernel g 1( ) g 2( ) 1 2 3 4 5 1 2 3 4 5 : h=1WL h=2 g 1( ) g 2( ) 1,2 2,134 3,24 4,235 5,4 1,24 2,14 3,24 4,135 5,4 3 3,24 k g1 1( ) ,g1 2( ) ( )= (g1 (1) )(g1 (2) ) = (1,1,2,1,1, 1,0,1,0,2,0,1) (1,1,1,1,1, 0,1,0,1,1,1,1) =1+1+ 2 +1+1 + 0 + 0 + 0 + 0 + 2 + 0 +1 = 8 5 3
24. 24. 3. Results
25. 25. in silico data 1 1 WL + Framework 1 GRNs Framework 2Supplementary Section S2 DREAM4 In Silico Network Challenge2009 10 5 5
26. 26. in silico data 2 21 3 5
27. 27. Framework2 WL kernel Framework1 WL kernel AUC ODE 1AUC AUC AUC mRNA AUC = Framework1 WL data not shown Fig. 2 in silico data 2
28. 28. S. pombe S. cerevisiae GRNs Fig. 3 100 ? 212%BioGRID gas1 gas1MBFcig2, mrc1, cdt2, rad12, msh6 157 + ?
29. 29. 4. Discussion
30. 30. Gas1 Zhang an Moret, 2010 WL Shortest passGraphlet Penfold, 2012, Calderhead and Girolami, 2009