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 BioinformaticsUCSC Genome BrowserOther 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 alpha-globin 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

embryonicfetaladult

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

• 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

Data on function from ENCODE

Genotype data with links to phenotype

Genes and pseudogenes

Comparative genomics

Find mutations associated with high HbF in HbVar

Query in HbVar for mutations associated with a similar phenotype

Start with information on an HPFH mutation upstream from HBG1

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 locus-specific 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

• Center for Comparative Genomics and Bioinformatics, Penn State University, University Park, PA

– Belinda Giardine, Ross Hardison, Webb Miller, Cathy Riemer

• Erasmus University, Rotterdam, Netherlands– George Patrinos

• Hospital Henri Mondor, Creteil, France– Henri Wajcman

• Boston University– David H.K. Chui

• IMBB, Crete, Greece– Nick Anagnou

• Macedonian Academy of Sciences and Arts, RCGEB, Skopje, Macedonia– Georgi D. Efremov

• Weatherall Institute of Molecular Medicine, Oxford UK– Richard Gibbons, Doug Higgs, Jim Hughes

• Johns Hopkins University School of Medicine, Baltimore, MD– Garry Cutting, Andrew P. Feinberg

• Center for Biomolecular Science and Engineering, University of California, Santa Cruz, CA

– Fan Hsu, Jim Kent, Andrew Kern, Robert Kuhn, Heather Trumbower