Increased HLA class I and II diversity as 72 novel alleles are identified in volunteers for the National Marrow Donor Program Registry in 2010

AbstractSeventy-two novel human leukocyte antigen (HLA) class I and class II allelesare described from volunteers for the ‘Be The Match Registry ® ’: 17 HLA-Aalleles, 12 HLA-C alleles, 31 HLA-B alleles and 12 HLA-DRB1 alleles. Forty-six(∼64%) of the 72 novel alleles are single-nucleotide substitution variants whencompared with their most homologous allele. Five of these single-nucleotide variantsare silent substitutions and one creates a non-expressed allele (B*44:108N). Theremaining novel alleles differ from their most similar allele by two to five nucleotidesubstitutions. One of the novel HLA-C alleles (C*07:150Q) is of questionableexpression due to an insertion of 21 nucleotides starting at codon 143 that adds sevenamino acids to exon 3. An inter-locus gene conversion may have created the novelallele HLA-A*23:31 that shares its codon differences with HLA-B*07:28. Some ofthe new alleles encode novel codons and unique amino acid changes at polymorphicpositions in the HLA-A (codons 116 and 150), HLA-C (codon 114), HLA-B (codons11, 21, 35, 42, 48, 73, 98 and 170) and HLA-DRB1 (codon 29) loci.Seventeen novel human leukocyte antigen A (HLA-A) alleleswere identified by DNA sequencing: two A* 01 (*01:01:20and *01:66), three A*02 (*02:263, *02:267 and *02:271),two A*03 (*03:88 and *03:89), one A*11 (*11:70), threeA*23 (*23:01:04, *23:30 and *23:31), one A*24 (*24:131),one A*30 (*30:44), two A*31 (*31:01:08 and *31:40) andtwo A*68 (*68:03:03 and 68:54). The cells carrying thesealleles along with ethnicity and other HLA locus typings arelisted in Table 1 (1). Ten of the 17 new HLA-A alleles wereobserved in individuals who self-described their ancestry asNorth American, White-European or White-Middle Eastern.Two novel HLA-A alleles each were found in individualsself-described as African American or as Chinese. Individualsself-described as African Black, Vietnamese and Hispanic-Caribbean Central American each contributed a single novelHLA-A allele. One of the novel alleles (HLA-A*23:31) wasobserved in three separate individuals of African Americanancestry and a haplotype carrying this new allele couldbe predicted: A*23:31, C*04, B*44 and DRB1*13. Theremaining novel HLA-A locus alleles were observed onlyonce in the course of this study.Eleven of the 17 new HLA-A alleles are single-nucleotidevariants when compared with their most homologous allele(Table 2) (2, 3), of which seven result in an amino acid changeand four result in a silent substitution. The remaining six novelHLA-A alleles differ from their most similar allele by two tofive nucleotide substitutions that cause one to four amino aciddifferences. One of the new HLA-A alleles may have beenderived by an intra-locus gene conversion. HLA-A*03:89that differs from A*03:23:01 by four nucleotides (Table 2)shares the altered codons 2 (TCT), 24 (GCA), 70 (CAC)and 74 (CAC) and the surrounding sequence with alleles inthe A*02 group. Another of the new HLA-A alleles waspossibly derived by an inter-locus gene conversion with aHLA-B allele. HLA-A*23:31 differs from A*23:01:01 by fivenucleotides from codons 105 to 116. This codon combinationis unique in the HLA-A locus. However, these codons anda small segment of surrounding sequence are shared with