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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.

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Presentation on theme: "Analyzing Gene Relationships for Down Syndrome with Labeled Transition Graphs Neha Rungta, Hyrum Carroll, Eric Mercer, Mark Clement, and Quinn Snell Computer."— Presentation transcript:

1 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

2 Goal  How is the SHH gene related to chromosome 21 genes?

3 Trisomy causes DS  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 features ndss.org

4 Decreased Cerebellum Size  P0 is 0 postnatal days  Same cerebellum size at birth  Different cerebellum size in 6 days  Difference persists NormalDS Mice

5 SHH

6 Small Jaw

7 Modifier gene - SHH  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

8 Hedgehog signal Pathway Image from genome.jp

9 State of art pathway analysis  Cyctoscape  Reactome  Bind  Visualize gene regulatory networks  Basic query mechanisms to probe structure

10 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

11 Our Approach  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

12 Kegg Database  1 st source of data  Largest and most comprehensible database  175 pathways 12,000 genes - human genome  Pictorial and XML representation

13 PubMed Abstracts  2 nd source of data  Premier journal for bio-medical articles  Bunescu et al. extract gene relationships using natural language processing algorithm

14 Graph Construction  Take a gene regulatory pathway  Abstract away the reactions and compounds  Create intra-pathway gene connections  Create inter-pathway gene connections  Add PubMed relations

15 Example PTCH HSP SHHPTCH GLIWNT1 Hedgehog Signaling Pathway (HSP) PTCH TP53 Basal Cell- Carcinoma (BCC) A2MLRP1 APOEAPP Alzheimer's Disease (AD) A2M - WNT1 PubMed Relations SHH HSP WNT1 HSP GLI HSP PTCH BCC TP53 BCC A2M AD LRP1 AD APOE AD APP AD

16 Example PTCH HSP SHHPTCH GLIWNT1 Hedgehog Signaling Pathway (HSP) PTCH TP53 Basal Cell- Carcinoma (BCC) A2MLRP1 APOEAPP Alzheimer's Disease (AD) A2M - WNT1 PubMed Relations SHH HSP WNT1 HSP GLI HSP PTCH BCC TP53 BCC A2M AD LRP1 AD APOE AD APP AD

17 Example PTCH HSP SHHPTCH GLIWNT1 Hedgehog Signaling Pathway (HSP) PTCH TP53 Basal Cell- Carcinoma (BCC) A2MLRP1 APOEAPP Alzheimer's Disease (AD) A2M - WNT1 PubMed Relations SHH HSP WNT1 HSP GLI HSP PTCH BCC TP53 BCC A2M AD LRP1 AD APOE AD APP AD

18 Example PTCH HSP SHHPTCH GLIWNT1 Hedgehog Signaling Pathway (HSP) PTCH TP53 Basal Cell- Carcinoma (BCC) A2MLRP1 APOEAPP Alzheimer's Disease (AD) A2M - WNT1 PubMed Relations SHH HSP WNT1 HSP GLI HSP PTCH BCC TP53 BCC A2M AD LRP1 AD APOE AD APP AD

19 Example PTCH HSP SHHPTCH GLIWNT1 Hedgehog Signaling Pathway (HSP) PTCH TP53 Basal Cell- Carcinoma (BCC) A2MLRP1 APOEAPP Alzheimer's Disease (AD) A2M - WNT1 PubMed Relations SHH HSP WNT1 HSP GLI HSP PTCH BCC TP53 BCC A2M AD LRP1 AD APOE AD APP AD

20 Example PTCH HSP SHHPTCH GLIWNT1 PTCH TP53 A2MLRP1 APOEAPP A2M - WNT1 Hedgehog Signaling Pathway (HSP) Basal Cell- Carcinoma (BCC) Alzheimer's Disease (AD) PubMed Relations SHH HSP WNT1 HSP GLI HSP PTCH BCC TP53 BCC A2M AD LRP1 AD APOE AD APP AD

21 Example PTCH HSP SHHPTCH GLIWNT1 A2MLRP1 APOEAPP PTCH TP53 A2M - WNT1 Hedgehog Signaling Pathway (HSP) Basal Cell- Carcinoma (BCC) Alzheimer's Disease (AD) PubMed Relations SHH HSP WNT1 HSP GLI HSP PTCH BCC TP53 BCC A2M AD LRP1 AD APOE AD APP AD

22 Analysis  12,000 nodes  1 million edges  90% connections due to common genes  Large unique shortest paths  Random BFS allows sampling

23 Random BFS PTCH HSP SHH HSP WNT1 HSP GLI HSP PTCH BCC TP53 BCC A2M AD LRP1 AD APOE AD APP AD

24 Random BFS PTCH HSP SHH HSP WNT1 HSP GLI HSP PTCH BCC TP53 BCC A2M AD LRP1 AD APOE AD APP AD 6 steps

25 Random BFS PTCH HSP SHH HSP WNT1 HSP GLI HSP PTCH BCC TP53 BCC A2M AD LRP1 AD APOE AD APP AD 6 steps

26 Metric SHHabChr. 21 (x)SHHacChr. 21 (y)SHHadChr. 21 (z)

27 Metric SHHabChr. 21 (x)SHHacChr. 21 (y)SHHadChr. 21 (z)

28 Gene Relations

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32 Conclusions & Future Work  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

33 Questions ?


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