Transcript HbVar_PhenCode - Center for Comparative Genomics and

ENCODE to PhenCode: Combining HbVar
with Genomic and ENCODE annotations
Ross Hardison, representing:
Curators and staff of HbVar and GenPhen
PSU Center for Comparative Genomics and Bioinformatics
UCSC Genome Browser
Other collaborators
Importance of inherited hemoglobinopathies
• Most common inherited diseases in humans
• Hemoglobin variants can lead to:
– Pathologies such as sickle cell disease, unstable hemoglobins,
altered oxygen affinities
– No alteration in phenotype
– Some protection against malarial parasite
• Thalassemias
– Inherited anemias resulting from deficit in production of alphaglobin or beta-globin
• Hereditary persistence of fetal hemoglobin
– HPFH
– Maintain HbF in adult life
Developmental regulation of the HBB gene complex
transcription, in erythroid cells
adult
fetal
embryonic
locus control region
Beta-globin genes and TRIM genes are islands
within a sea of OR genes
Example of information about the Hispanic
thalassemia deletion from HbVar
HbVar: Hemoglobin variants and
thalassemia mutations
• Began as Prof. Titus Huisman’s Syllabus of
Hemoglobin Variants and Syllabus of
Thalassemia Mutations
• Converted to on-line resource about 1997
• Major curators now:
– Henri Wajcman, Ph.D.
– George Patrinos, M.D., Ph.D.
– David Chui, M.D.
Current status of HbVar
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Type
Count
Total entries in database
1233
Total hemoglobin variant entries
926
Total thalassemia entries
355
Entries both variant and thalassemia
48
Entries involving the alpha1 gene
250
Entries involving the alpha2 gene
286
Entries involving the beta gene
687
http://www.bx.psu.edu/
GenPhen
• Records genotype and published phenotype data
– Hemoglobin variants
– Thalassemias
– HPFH
HbVar Query Page
Find large deletions leading to thalassemia
Combine data on history page
View results on UCSC Genome Browser
http://genome.ucsc.edu/
Use UCSC Genome Browser as a portal to
locus specific data
• MANY more people go to genome browsers than
to locus specific databases
• Data on variants and mutations can be easily
displayed as a track on the browser
• Information from other resources can be readily
be integrated with variation information
– E.g. ENCODE data on transcription, factor binding
sites, chromatin modifications, etc.
– Viewed on Genome Browser
– Accessed via Table Browser
Prototype Browser interface for HbVar
Etc.
Filters can be applied on “Details” page
View focused on deletions in noncoding regions
Details about an individual mutation
UCSC Genome Browser is a portal to HbVar and an
integrator of functional, genomic and genotype data
Comparative genomics
Genes and pseudogenes
Genotype data with links
to phenotype
Data on function
from ENCODE
Find mutations associated with high HbF in HbVar
Start with information on
an HPFH mutation
upstream from HBG1
Query in HbVar for
mutations associated
with a similar phenotype
Discover that some of
the mutations are in a
linked gene, HBB
Giant RNAs, 32 yr ago
Long transcripts run through OR genes into
globin genes
Human phenotype track in HBA complex
Etc.
Invite other databases to join the Browser portal
Future prospects
• Add more loci
– WayStation: Community-wide Database for participating locusspecific databases
– Individual databases
– Harvest protein variants from SwissProt (Fan Hsu, UCSC)
• Better display of phenotype information in browser
– Genotype is naturally displayed in genome coordinates
– Effects on expression levels, development, cell cycle progression,
etc need additional dimensionality
– Current solution is crude (put it on a different page)
• Improve integration among the datasets
– Table Browser to obtain data
– Integration tools at Table Browser and Galaxy, other servers
Collaborating Institutions and People
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Center for Comparative Genomics and Bioinformatics, Penn State University,
University Park, PA
– Belinda Giardine, Ross Hardison, Webb Miller, Cathy Riemer
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Erasmus University, Rotterdam, Netherlands
– George Patrinos
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Hospital Henri Mondor, Creteil, France
– Henri Wajcman
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Boston University
– David H.K. Chui
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IMBB, Crete, Greece
– Nick Anagnou
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Macedonian Academy of Sciences and Arts, RCGEB, Skopje, Macedonia
– Georgi D. Efremov
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Weatherall Institute of Molecular Medicine, Oxford UK
– Richard Gibbons, Doug Higgs, Jim Hughes
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Johns Hopkins University School of Medicine, Baltimore, MD
– Garry Cutting, Andrew P. Feinberg
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Center for Biomolecular Science and Engineering, University of California,
Santa Cruz, CA
– Fan Hsu, Jim Kent, Andrew Kern, Robert Kuhn, Heather Trumbower