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Analyzing Gene Relationships for Down Syndrome with Labeled
Transition Graphs
Neha Rungta, Hyrum Carroll, Eric Mercer, Mark Clement, and Quinn Snell
Computer Science Department,
Brigham Young University, Provo, UT
Randall Roper
Department of Biology and Indiana University for Regenerative Biology & Medicine, Indiana University-Purdue University,
Indianapolis, IN, USA
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How is the SHH gene related to chromosome 21 genes?
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1/600 Live Births
220,000 individuals per year
Extra copy of Chr. 21
A subset of 80 clinical features
Some common physical features
Varying degrees of manifestation
Modifier genes affect featuresndss.org
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QuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture. Decreased Cerebellum Size
P0 is 0 postnatal days
Same cerebellum size at birth Different cerebellum size in 6 days
Difference persists
Normal DS Mice
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SHH is a modifier gene Affects DS characteristics Is key factor in a lot of development How the SHH gene is linked to Chr. 21? Analyze relationships
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Image from genome.jp
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Cyctoscape Reactome Bind Visualize gene regulatory networks Basic query mechanisms to probe structure
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QuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture.Formal Verification approaches
Heath et al. (`06), Kuwahara et al.(`06), Kwiatkowska et al.(`05), and Dill et al.(`05).
Models a single network in isolation Predicts pathway behaviors Models the different reactions and their rates
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Abstracts a large amount of information Connects different networks Single labeled transition graph Exhaustive search with a random BFS Find relations between SHH and Chr. 21
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1st source of data Largest and most comprehensible database 175 pathways 12,000 genes - human genome Pictorial and XML representation
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2nd source of data Premier journal for bio-medical articles Bunescu et al. extract gene relationships
using natural language processing algorithm
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Take a gene regulatory pathway Abstract away the reactions and compounds Create intra-pathway gene connections Create inter-pathway gene connections Add PubMed relations
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QuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture. Example
PTCHHSP
SHH PTCH
GLI WNT1
Hedgehog Signaling Pathway (HSP)
PTCH
TP53
Basal Cell-Carcinoma (BCC)
A2M LRP1
APOE APP
Alzheimer's Disease(AD)
A2M - WNT1
PubMed Relations
SHHHSP
WNT1HSP
GLIHSP
PTCHBCC
TP53BCC
A2MAD
LRP1AD
APOEAD
APPAD
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QuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture. Example
PTCHHSP
SHH PTCH
GLI WNT1
Hedgehog Signaling Pathway (HSP)
PTCH
TP53
Basal Cell-Carcinoma (BCC)
A2M LRP1
APOE APP
Alzheimer's Disease(AD)
A2M - WNT1
PubMed Relations
SHHHSP
WNT1HSP
GLIHSP
PTCHBCC
TP53BCC
A2MAD
LRP1AD
APOEAD
APPAD
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QuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture. Example
PTCHHSP
SHH PTCH
GLI WNT1
Hedgehog Signaling Pathway (HSP)
PTCH
TP53
Basal Cell-Carcinoma (BCC)
A2M LRP1
APOE APP
Alzheimer's Disease(AD)
A2M - WNT1
PubMed Relations
SHHHSP
WNT1HSP
GLIHSP
PTCHBCC
TP53BCC
A2MAD
LRP1AD
APOEAD
APPAD
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QuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture. Example
PTCHHSP
SHH PTCH
GLI WNT1
Hedgehog Signaling Pathway (HSP)
PTCH
TP53
Basal Cell-Carcinoma (BCC)
A2M LRP1
APOE APP
Alzheimer's Disease(AD)
A2M - WNT1
PubMed Relations
SHHHSP
WNT1HSP
GLIHSP
PTCHBCC
TP53BCC
A2MAD
LRP1AD
APOEAD
APPAD
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QuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture. Example
PTCHHSP
SHH PTCH
GLI WNT1
Hedgehog Signaling Pathway (HSP)
PTCH
TP53
Basal Cell-Carcinoma (BCC)
A2M LRP1
APOE APP
Alzheimer's Disease(AD)
A2M - WNT1
PubMed Relations
SHHHSP
WNT1HSP
GLIHSP
PTCHBCC
TP53BCC
A2MAD
LRP1AD
APOEAD
APPAD
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QuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture. Example
PTCHHSP
SHH PTCH
GLI WNT1
PTCH
TP53
A2M LRP1
APOE APP
A2M - WNT1
Hedgehog Signaling Pathway (HSP)
Basal Cell-Carcinoma (BCC)
Alzheimer's Disease(AD)
PubMed Relations
SHHHSP
WNT1HSP
GLIHSP
PTCHBCC
TP53BCC
A2MAD
LRP1AD
APOEAD
APPAD
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QuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture. Example
PTCHHSP
SHH PTCH
GLI WNT1
A2M LRP1
APOE APP
PTCH
TP53
A2M - WNT1
Hedgehog Signaling Pathway (HSP)
Basal Cell-Carcinoma (BCC)
Alzheimer's Disease(AD)
PubMed Relations
SHHHSP
WNT1HSP
GLIHSP
PTCHBCC
TP53BCC
A2MAD
LRP1AD
APOEAD
APPAD
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QuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture. Analysis
12,000 nodes 1 million edges 90% connections due to common genes Large unique shortest paths Random BFS allows sampling
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QuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture. Random BFS
PTCHHSP
SHHHSP
WNT1HSP
GLIHSP
PTCHBCC
TP53BCC
A2MAD
LRP1AD
APOEAD
APPAD
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QuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture. Random BFS
PTCHHSP
SHHHSP
WNT1HSP
GLIHSP
PTCHBCC
TP53BCC
A2MAD
LRP1AD
APOEAD
APPAD
6 steps
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QuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture. Random BFS
PTCHHSP
SHHHSP
WNT1HSP
GLIHSP
PTCHBCC
TP53BCC
A2MAD
LRP1AD
APOEAD
APPAD
6 steps
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SHH a b Chr. 21 (x)
SHH a c Chr. 21 (y)
SHH a d Chr. 21 (z)
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QuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture. Metric
SHH a b Chr. 21 (x)
SHH a c Chr. 21 (y)
SHH a d Chr. 21 (z)
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QuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture. Gene Relations
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QuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture. Gene Relations
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QuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture. Gene Relations
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QuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture. Gene Relations
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New technique to combine different gene regulatory networks with a transition graph
Discovers new relations
More refined analysis with transition graphs Use mu-calculus to pose interesting questions
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Questions ?