Download 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)