R. Hardison, D.H.K. Chui, T.H.J. Huisman, M.F.H. Carver, T.P. Molchanova, G.D. Efremov, E. Baysal, H. Lehväslaiho, C. Riemer, and W. Miller
rch8@psu.edu
Penn State University, University Park, PA; McMaster University, Hamilton, Ontario, Canada; Medical College of Georgia, Augusta, GA;Macedonian Academy of Sciences and Arts, Skopje, Maceonia; European Bioinformatics Institute, Cambridge, UK
Mutations in the human globin genes cause the most common inherited diseases known in man. Alterations in their coding sequences can lead to the formation of variant hemoglobins, some of which (e.g. Hb S) have abnormal properties, such as polymerization, increased or decreased oxygen affinity, instability, and others. Other mutations affect the expression of globin genes; the resultant decrease or absence of globin chain production causes disorders known as the thalassemias. Additional natural mutations, such as Hb E, lead to both formation of a hemoglobin variant and also decreased globin chain production. More than 1000 natural mutations in the human globin genes are currently known, and more are still being discovered. Taken together, they form a significant body of information, providing insights into the regulation of globin gene expression and the function of the hemoglobin molecule.
Information on these natural mutations has been compiled into two Syllabi. The Syllabus of Human Hemoglobin Variants (1996) describes each of more than 700 abnormal hemoglobins resulting from alterations in the a, b-, g- and d-globin chains, as well as special abnormalities, such as double mutations, hybrid chains, elongated chains, deletions, insertions, etc. The Syllabus of Thalassemia Mutations describes more than 315 determinants of thalassemia and HPFH, including alleles for b-, d-, g-, d-b- and a-thalassemia. Each entry of both Syllabi provides amino acid and/or DNA sequence alterations, hematological and clinical data, methodology for characterization, frequency and ethnic distribution of occurrence, and appropriate literature references. For the hemoglobin variants, functional properties and stability of the hemoglobin are also recorded.
Both Syllabi are available in printed form from The Sickle Cell Anemia Foundation and are accessible over the WorldWide Web via the Globin Gene Server at http://globin.cse.psu.edu (Chui et al. 1998, Blood 91: 2643; Hardison et al. 1998, Hemoglobin 22: 113; Hardison et al., 1998, Genomics 47: 429). For the electronic versions of these Syllabi, a simple query interface allows the user to find all entries containing a designated string (word or phrase), so that one can find, e.g., all variants in resulting from mutations in codon 6 of the b-globin chain, or all mutations found in Indian populations. The records on hemoglobin variants have been transformed into a more formal database called HBVARS, which can be accessed along with a network of locus-specific mutation databases (and other relevant databases) via the SRS interface at the European Bioinformatics Institute (http://srs.ebi.ac.uk/). This allows integration of the information on hemoglobin mutations into a wide range of studies of human mutations and genetics, using a rather powerful query engine.
Information about regulatory loci in the mammalian beta-globin gene clusters is now available in a database of experimental results on gene expression called dbERGE (Riemer et al. 1998, Genomics, in press). To date, the database has been focused on LCR function. Very detailed data are recorded, and some simple queries can be made via a forms-based interface. Currently, more complex queries require consultation with our database administrator, but future improvements to the programming language and the network browsers should allow them to be formulated easily and independently by users.
We continue to provide updated alignments of sequences of the mammalian b-globin gene clusters, and we plan to add alignments of the available regions of the alpha-globin gene clusters. Several tools are available for finding and viewing conserved sequences within the alignments. This work is supported by PHS grants LM05773, LM05110, DK27635, and The Sickle Cell Anemia Foundation (Augusta, GA).
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