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Variome meets the Genome: Challenges and Opportunities

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Variome meets the Genome: Challenges and Opportunities ... Blood/Buccal cells. DNA isolation. PCR. Multiplex PCR for. rapid screening at 5 loci. SBE (SNaPshot) ... – PowerPoint PPT presentation

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Title: Variome meets the Genome: Challenges and Opportunities


1
Variome meets the Genome Challenges and
Opportunities
Human Variome Project (HVP) Forum HGM2008
Satellite meeting 27th September 2008
Mitali Mukerji Institute of Genomics and
Integrative Biology CSIR, Delhi, India
2
  • SCA as a case study
  • Clinically and genetically heterogeneous group of
    neurodegenerative disorders.
  • Characterised by progressive cerebellar and
    spinal cord dysfunction.
  • Clinical Features Gait ataxia, Dementia,
    Dysphagia, Opthalmoplegia, Retinal degeneration.

Mapped loci (disease gene unknown)
3
Why LSDB for ataxia ??
SCAs Shows the phenomenon of Anticipation
Only genotype-phenotype correlation consistently
observed in all populations is anticipation
Confounders in clinical classification
  • Due to considerable overlap between the
    symptomatology clinical classification is
    difficult in SCAs
  • Clinical features varies among population of
    different ethnic origin
  • At early stage disease show characteristic
    distinguishable features but with increasing
  • duration symptoms converges to overlapping
    phenotypes
  • Not all subtypes reported in populations e.g
    only six SCAs in India
  • Some SCAs unique to populations - e.g SCA6 and
    DRPLA in Japan, SCA12 in India

4
Total SCA families- 450 Characterized SCAs-
201 Uncharacterized 249
Prevalence and frequencies of ataxia in India
5
  • Advantage of an LSDB for ataxia
  • provide valuable insight into phenotypic
    variability, locus heterogeneity of SCAs
    geographical and ethnicity specific variable
    expression
  • Genotype phenotype correlation between repeat
    lengths and more detailed clinical assessment in
    SCAs among different populations would help
    establish accurate clinical classification and
    planning optimal treatment/disease management
    strategies
  • It would help compare the variation in
    neurological features among different populations
    and thus enable identification of modifying
    factors responsible for phenotypic variability
  • starting point for understanding the molecular
    correlates of phenotypes in ataxia which is a
    multi locus disease where related molecular
    mechanisms converge to overlapping phenotypes.
  • Novel candidate regions can be identified

6
Phenotype data
Public Submissions
XML Interface
Other Global Databases
PML Central
Blood/Buccal cells DNA isolation
PCR Multiplex PCR for rapid
screening at 5 loci SBE (SNaPshot)
Fragment analysis Direct Sequencing (ABI
sequencer 3130xl)
SCA1 SCA2 SCA3 SCA6 SCA7 SCA8 SCA12 DRPLA SCA17
Indian Genome Variation Database
  • Repeat No. at respective loci
  • Other sequence variants
  • Haplotypes
  • HGV accredited nomenclature

Mohd Faruq, Vinod Scaria Mitali Mukerji
7
Spino-Cerebellar Ataxia Locus Specific Variation
Database
Built on the Leiden Open Variation Database
architecture Feature for Open Submission and
Curation of Variants and Phenotypes XML
interoperability for exchange of
genotype-phenotype details
8
LSDB for SCAs
Patient Data
Variant Data
Standardised Variation annotation as per HGVS
Nomenclature Committee
9
Advanced Search Interfaces
10
Weakness of LSDB
  • LSDB holds locus specific information for a
    particular gene/disease and mutations are mapped
    and curated as static information on a reference
    sequence
  • The current configuration of LOVD does not allow
    for dynamic exchange of data from LSDB to genome
    level
  • The contextual effect of the locus in the genome
    perspective is lost
  • The locus specific information is limited by the
    knowledge of the curator
  • Locus/Disease with multiple interacting
    partners/genes cannot be visualised
    comprehensively

11
PP2A Assembly

PPP2R2B encodes subunit of the holoenzyme
assembly of PP2A
12
Association of PP2A in Various Diseases
LTD
Sequester in SCA 1 Inclusion
Cellular Growth, Differentiation, Development
  • Substrate
  • Cellular Protein
  • (Tau/Vimentin)
  • Viral Proteins
  • Signaling Cascade
  • MAPK
  • JAK/SAPK

Anp32a/Lanp Regulates PP2A
PKCs
PKB/Akt
Alteration In Activity Of PP2A
Alteration of Cellular Growth, Differentiation,
Development
  • Hyper-phosphorylation of Tau
  • Microtubule Destabilization
  • Modification of Synapse Structure

Dysregulated signaling cascade
Implications In SCA 1 Transgenic Mice.
SCA 14
SCA 1
Cancerous Growth (Breast Cancer, Lung Carcinoma,
etc.)
Neurodegeneration (eg. Alzheimer disease)
13
Genomic structure of PPP2R2B and alternately
spliced transcripts
Protein varient / divergent N termini
Transcripts alternate 5 splice varients
Bbeta1
Bbeta2
Bbeta3
Bbeta1
Bbeta4
Bbeta5 (predicted)
Bbeta7 (pridicted)
Bbeta6 (predicted)
Holmes et. al.
14
c.279CAG1055
g.202694CAG1055
15
Adapting a Wiki based approach to LSDB
Vinod Scaria Sridhar Sivasubbu _at_ IGIB
16
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17
Approach
LSDB Genome centric
LSDB Locus centric
Variations Mapped as static information
Dynamically integrated into genome
Community participation
Wiki
18
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