Locking Horns with Functional Genomics Projects: So far and So forth

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Locking Horns with Functional Genomics Projects
So far and So forth

• Anil Jegga
• Pediatric Informatics

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Bioinformatics Projects Under Progress
Trafac PipeLine
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Trafac Re-collection
Comparative Analysis of Homologous Sequences
After gt900 Myrs of divergence essential
functional elements remain conserved! E.g. PAX6
Human Vs Puffer fish (Fugu rubripes)
http//bio.cse.psu.edu/Multipipmaker
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Limitations
Scope

• Cis-elements that are not conserved across the
  orthologous genes cannot be identified even
  though they occur in regions of sequence
  similarity across the species.
• Cis-elements that occur in non-aligned genomic
  regions across the two species cannot be
  identified by this approach.

• A powerful filter that can aid in the
  identification of potential functional
  cis-clusters.
• Search not limited to just the upstream promoter
  region.
• The novel cis-element modules may be useable as
  probes for genome wide annotation of additional
  potential regulatory regions.

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46 Matrix families with a frequency of occurrence
of 6
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Fetching Genomic Seq
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• Trafac PipeLine
• About 700 genes 3 months ago Now, gt5000!
• Will be the first of its kind (A genome-wide
  gene-centric approach)
• A readily available potential resource database
  for unraveling the secrets of co-expression of
  genes.
• Building up a regulatory module database based on
  expression pattern, functional classification or
  phenotype

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Regulomorph (Regulatory Polymorphisms)
CTNND2 catenin (cadherin-associated protein),
delta 2) 1225 AA, 4746 bp mRNA
Genomic Sequence gt1 million bp 1st Intron gt192
kb!!
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Visualization of nsSNPs on Protein Domains
Structures
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• Variant at 280 (Arg lt-gt His) was associated with
  a slightly increased prostate cancer risk
• Haplotype A (194Trp, 280Arg, and 399Arg) was
  associated with significant reduction in gastric
  cancer risk whereas haplotype D (194Arg, 280Arg,
  and 399Arg alleles) was a risk type for gastric
  cancer (adjusted OR1.57, 95 CI0.93-2.65).

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Mapping Non-Synonomous SNPs onto Conserved
Protein Domains
OGG1 8-oxoguanine DNA glycosylase
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GO Term Cell Cycle Checkpoint (GO0000075) (18
Genes Hs)

• Keyword List
• Interact(s)
• Inhibit(s)
• Phosphorylate(s)..

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730 Records
307 Records
Text Processing Tool

• OmniViz
• ExPASy Tools
• AcroMed
• AbXtract
• MedMiner
• Protein Annotators Assistant
• XplorMed

• Filter Publications
• Parse Publication
• Parse Content
• Extract Relationships
• Store Relationships

Interactions/Relations
PathMaker
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PathMaker Palette
Nodes
Activity (Pathway Step Arc)
Active Entitites
CV Term
ATM
PLK3
Gene Ontology Sequence Ontology Variation/SNPs Dis
ease Ontology Pathology Pharmacology Anatomy Devel
opment Expressionetc.
TP53
CHEK2
CDKN1A
CDK2
CDC25C
CDC2
User Selected and/or Added to
PathMaker Canvas
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PathMaker

• Views
• Show all Pathways in the db or Pathways by Source
  (KEGG, Biocarta, etc)
• Pathways by classification (regulatory/metabolic)
• Pathways by phenotype, by User Group, by Organism
• User Edited Pathways

• Queries
• Give me a list of all genes (with annotations)
  participating in this pathway. Annotations
  include
• Gene Symbol, Gene description, List of
  Ontologies, List of other pathways the gene is
  involved in, List of SNPs, List of diseases
  associated with this pathway.
• Given a gene, show all the pathways in the
  database it is involved in
• Given a phenotype (disease), show all the
  associated pathways
• Given an ontology term, show the corresponding
  pathways
• Search by any term (any of the cv or related term)

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Whats Next?

• Addition of more groups of genes to the database
  A Continuous process (From 5000 to 40000)
• Database of cis-acting regulatory modules
  (Cis-Mols) Based on
• Gene Expression Pattern
• Tissue Specificity
• Gene Ontology Functionalities
• Multiple Comparison of Genomic DNA Sequences
• Regulomorphs (Regulatory SNPs)

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The Team
Acknowledgements
Anil Jegga Ashima Gupta Sivakumar
Gowrisankar Jing Chen Sheshukalyan Andra Bhuvana
Sakthivel Sue Kong Jim Carman Bruce Aronow
NIEHS U01 ES11038 CMGCC
Howard Hughes Medical Institute