2. 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

3. 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

4. Developmental regulation of the HBB gene complex transcription, in erythroid cells embryonicfetaladult locus control region

5. Beta-globin genes and TRIM genes are islands within a sea of OR genes

6. Example of information about the Hispanic thalassemia deletion from HbVar

7. 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.

8. Current status of HbVar TypeCount Total entries in database1233 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/

9. GenPhen Records genotype and published phenotype data –Hemoglobin variants –Thalassemias –HPFH

10. HbVar Query Page

11. Find large deletions leading to thalassemia

12. Combine data on history page

13. View results on UCSC Genome Browser http://genome.ucsc.edu/

14. 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

15. Prototype Browser interface for HbVar Etc.

16. Filters can be applied on “Details” page

17. View focused on deletions in noncoding regions

18. Details about an individual mutation

19. 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

20. 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

21. Giant RNAs, 32 yr ago

22. Long transcripts run through OR genes into globin genes

23. Human phenotype track in HBA complex Etc.

24. Invite other databases to join the Browser portal

25. 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

26. 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