Nomenclature for factors of the HLA system, 2004 (2005)

Following the decision to hold their next full meeting after the 14th International Histocompatibility Workshop in 2005, the WHO Nomenclature Committee for Factors of the HLA System has decided to publish an interim report listing updated tables of alleles including those assigned since the publication of the last full report in 2002 (1). The alleles named during the period follow the principles established in previous reports (1–17). As emphasized in previous reports, there are required conditions for acceptance of new sequences for official names. Where a sequence is obtained from cDNA, or where PCR products are subcloned prior to sequencing, several clones should have been sequenced. Sequencing should always be performed in both directions. If direct sequencing of PCR amplified material is performed, products from at least two separate PCR reactions should have been sequenced. In individuals who are heterozygous for a locus, and where one of the alleles is novel, the novel allele must be sequenced in isolation from the second allele. Thus an allele sequence which is derived using a sequence based typing (SBT) methodology, where both alleles of a heterozygous individual are sequenced together, is insufficient evidence for assignment of an official designation. Sequence derived solely from the primers used to amplify an allele should not be included in the submitted sequence. Where possible, a novel sequence should be confirmed by typing of genomic DNA using a method such as PCR-SSOP or PCR-SSP. Where a new sequence contains either a novel mutation or a previously unseen combination of nucleotides (sequence motif), this must be confirmed by a DNA typing technique. This may require the use of newly designed probes or primers to cover the new mutation; these reagents should also be described. An accession number in a databank should have been obtained. Sequences may be submitted to the databases online at the following addresses: EMBL: http://www.ebi.ac.uk/Submissions/index.html GenBank: http://www.ncbi.nlm.nih.gov/GenBank/index.html DDBJ: http://www.ddbj.nig.ac.jp/sube.html Full-length sequences are preferable though not essential; the minimum requirements are complete exons 2 and 3 for an HLA class I sequence and complete exon 2 for an HLA class II sequence. Where a novel sequence differs only within an intron or other non-coding part of the gene, a full length sequence must be obtained, which covers all coding and non-coding regions. In the absence of a full length genomic sequence from the most closely related allele, it may be required that this also be sequenced and submitted before a name can be assigned to the novel sequence. Where possible, a paper in which the new sequence is described should be submitted for publication. DNA or other material, preferably cell lines, should, wherever possible, be made available in a publicly accessible repository or alternatively, at least in the originating laboratory. Documentation on this will be maintained by the WHO Nomenclature Committee. Submission of a sequence to the WHO Nomenclature Committee should be performed using the online submission tool available at http://www.ebi.ac.uk/imgt/hla/subs/submit.html. Researchers are expected to complete a questionnaire relating to the sequence and provide a comparison of their new sequence with known related alleles. If the sequence cannot be submitted using the online web tools, researchers should contact [email protected] directly for details of alternative submission methods. Although at present it is only a recommendation that full-length sequences of the coding region of novel alleles be submitted it was widely felt that in the future this should become a requirement for submission. Such requirement would remove many of the currently encountered ambiguities in the assignment of names to alleles for which partial sequences have been submitted and should not be burdensome as sequencing techniques have improved substantially since the submission conditions were first devised. In cases where novel mutations or polymorphisms are detected in non-coding regions of the gene, it will be a requirement that full-length sequences be submitted of both the novel allele and its most closely related allele. It should be noted with some caution that cells from which only partial sequences have been obtained may later be shown to have different or novel alleles when further sequencing is performed. This is of particular importance in cases where partial sequences of what appears to be the same allele have been obtained from several different cells. In such cases, all cells studied have been listed in this report. Current practice is that official designations will be promptly assigned to newly described alleles in periods between Nomenclature Committee meetings, provided that the submitted data and its accompanying description meet the criteria outlined above. A list of the newly reported alleles is published each month in nomenclature updates in the journals Tissue Antigens, Human Immunology and the International Journal of Immunogenetics. The listing of references to new sequences does not imply priority of publication. The use of numbers or names for alleles, genes or specificities which pre-empt assignment of official designations by the Nomenclature Committee is strongly discouraged. The list of those genes in the HLA region considered by the WHO Nomenclature Committee is given in Table 1. A total of 422 HLA alleles has been named since the last report (1). The newly named alleles are shown in bold typeface in Tables 2–10. For HLA class I, 99 HLA-A, 137 HLA-B, 63 HLA-C, one HLA-E and one HLA-F alleles were named, making a total of 1180 class I alleles with official names. For HLA class II, 79 HLA-DRB1, three DRB3, one DRB4, three DRB5, six DQA1, eight DQB1, two DPA1, 17 DPB1, one DMB and one DOB alleles were named, making a total of 732 class II alleles with official names. Three MICA alleles were named bringing their total to 57. MICB alleles were named for the first time, with 18 alleles being assigned official names (Table 11). One TAP1 allele was named. The total number of alleles at each locus assigned with official names as of 31st December 2004 is given in Table 12. Errors had previously been detected within the HLA-E*0101 and E*0102 allele sequences; resequencing of the original material revealed that the corrected E*0102 allele was identical to the corrected E*0101 sequence. Consequently the E*0102 allele designation was deleted. A full list of all allele names which have been deleted is given in Table 13. As the database of HLA allele sequences has expanded, it has become increasingly difficult to maintain consistent linkage between allele names assigned on the basis of nucleotide sequences and the serological profiles of the encoded proteins. These difficulties are in part technological and in part due to the inherent biological properties of the HLA system. In the first category there is the increasing emphasis on DNA technology and consequent lack of a serological description for many newly discovered HLA alleles. In the second category it is the finding that a newly defined antigen does not comfortably fit within any known serological grouping. This is especially true of the DRB1*03, *11, *13, *14 and *08 family of alleles, for which the description of new alleles has revealed a continuum of allelic diversity rather than five discrete subfamilies. It should be stressed that, although a goal is to indicate the serological grouping into which an allele will fall, this is not always possible. Most importantly the allele name should be seen as no more than a unique designation. Column 2 of Tables 2–6 lists the serological specificities or antigens associated with the alleles, where this information is known. In most cases these data are based on the serological typing obtained for the cells which were sequenced for the individual alleles and from information submitted to the Committee. In many cases no serological information is available and the entry in the table has been left blank. This is also true for cases when the serological pattern associated with an expressed allele does not correspond to a single defined specificity. A comprehensive dictionary of antigen and allele equivalents is published periodically by the World Marrow Donor Association (WMDA) Quality Assurance Working Group on HLA Serology to DNA Equivalents (18–21). Where additional or superior serological data are available from the dictionary this has been included in column 2 of Tables 2–6 and the source of this information indicated. In the previous report, the extension of allele names to tackle three main problem areas with the HLA nomenclature was discussed. The first of these, expansion of the allele name from seven to eight digits to allow for up to 99 synonymous variants of each allele, was implemented immediately. As anticipated this has proved to have been a necessary change to the nomenclature and we already have 11 variants of the A*0201 allele named: A*020101 to A*020111, see Table 2. For HLA-DPB1 alleles, it was decided that once the DPB1*9901 allele had been named, any further alleles should be named within the existing system. The allele DPB1*9901 was named in October 2003 and following this alleles have been named sequentially within the existing system: DPB1*0102, DPB1*0203, DPB1*0302, DPB1*0403, DPB1*0502, DPB1*0602, DPB1*0802, DPB1*0902, see Table 7. In cases where the total number of coding variants exceeds 99, it was decided, that a second number series will be used to extend the first one. For example for the B*15 family of alleles, the B*95 series will be reserved and used to code for additional B*15 alleles. Consequently the next B*15 allele to be named following B*1599 will be B*9501. Likewise the A*92 series will be reserved as a second series for the A*02 allele family. While we have not yet had to implement this system, as the most recently assigned B*15 allele was B*1596, it is likely that it will be introduced shortly. The IMGT/HLA Sequence Database continues to act as the official repository for HLA sequences named by the WHO Nomenclature Committee for Factors of the HLA System (22, 23). The database contains sequences for all HLA alleles officially recognized by the WHO Nomenclature Committee for Factors of the HLA System and provides users with online tools and facilities for their retrieval and analysis. These include allele reports, alignment tools, and detailed descriptions of the source cells. The online IMGT/HLA submission tool allows both new and confirmatory sequences to be submitted directly to the WHO Nomenclature Committee. New releases of the database are made every three months, in January, April, July and October, with the latest version (release 2.8.0 January 2004) containing 1912 HLA alleles. The database may be accessed via the world wide web at http://www.ebi.ac.uk/imgt/hla. The IMGT/HLA Database is currently supported by the following organizations: Abbot Laboratories, the American Society for Histocompatibility and Immunogenetics (ASHI), the Anthony Nolan Trust (ANT), Biotest, Dynal Biotech, the European Federation for Immunogenetics (EFI), Genovision, Histogenetics, Innogenetics, LabCorp, the Marrow Foundation, the National Marrow Donor Program (NMDP), One Lambda and Tepnel Lifecodes. List of committee members involved in preparing this report: E D. Albert, Policlinic for Children, University of Munich, Germany (Chairman) S G. E. Marsh, Anthony Nolan Research Institute, London, UK (Rapporteur and Data Coordinator) W F. Bodmer, Cancer Research UK, Oxford, UK B Dupont, Sloan-Kettering Institute for Cancer Research, New York, USA H A. Erlich, Roche Molecular Systems, Alameda, USA D E. Geraghty, Fred Hutchinson Cancer Center, Seattle, USA C K. Hurley, Georgetown University, Washington, USA J A. Hansen, Fred Hutchinson Cancer Center, Seattle, USA B Mach, University of Geneva, Geneva, Switzerland W R. Mayr, University of Vienna, Vienna, Austria P Parham, Stanford University School of Medicine, Stanford, USA E Petersdorf, Fred Hutchinson Cancer Center, Seattle, USA T. Sasazuki, International Medical Center of Japan, Tokyo, Japan G M. Th. Schreuder, Leiden University Medical Center, Leiden, the Netherlands J L. Strominger, Harvard University, Cambridge, USA A Svejgaard, State University Hospital, Copenhagen, Denmark P I. Terasaki, Los Angeles, USA J Trowsdale, Cambridge University, Cambridge, UK R. E. Bontrop, Biomedical Primate Research Center, Rijswijk, the Netherlands New sequences should be communicated to Dr Steven Marsh via the sequence submission tool of the IMGT/HLA Database to receive official names, http://www.ebi.ac.uk/imgt/hla. The Committee would like to thank James Robinson, Matthew Waller and Sylvie Fail for their work with the IMGT/HLA Sequence database and their help in the preparation of tables for this report. Also thanked are Dr Peter Stoehr and the staff at the European Bioinformatics Institute for their continued support of the IMGT/HLA Database. We would also like to thank the many organizations who provide financial support for the IMGT/HLA database