Non-conservative substitutions distinguish previously uncharacterized HLA-A molecules.
The extent of class I HLA polymorphism is not yet realized, and to provide a glimpse of the HLA-A polymorphism which remains undetected, we have analyzed approximately 3,700 National Marrow Donor Program (NMDP) Donor/Recipient Pair Retrospective Study Samples with HLA-A DNA sequence-based typing (SBT). Seventeen new HLA-A alleles were detected, with a total of 19 nucleotide substitutions distinguishing these new alleles from their closest HLA-A relatives. Nearly all of the new alleles differ by single nucleotide substitutions; a majority of these substitutions can be explained by gene conversion events but 6 alleles likely originated by point mutation. Fifteen of the 19 nucleotide substitutions translate into amino acid differences in the molecule. Structurally, the inferred amino acid alterations were non-conservative in terms of chemical property, and most substitutions were positioned in 1 or more of the specificity pockets which determine peptide binding. Although these new alleles were identified in a primarily Caucasian sample population, 9 of the 17 new HLA-A alleles were found in samples of non-Caucasoid origin. A new allele detection rate of 1 in approximately 200 individuals in our data set would, therefore, be higher in a non-Caucasoid sample population. In summary, the single nucleotide substitutions that distinguish undetected HLA-A alleles translate into functionally distinct HLA-A molecules. Further studies of the role of HLA-A in transplantation, in disease association, and in evolution must therefore accommodate the discovery of new alleles differing by single nucleotides.
Hickman
H D
HD
Department of Microbiology & Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
Cavett
J W
JW
Ellexson-Turner
M E
ME
Sparkman
J N
JN
Bennett
T T
TT
Turner
S
S
Sidebottom
D A
DA
Trachtenberg
E A
EA
Confer
D L
DL
Hildebrand
W H
WH
D000483:Alleles; D019943:Amino Acid Substitution / Q000276:immunology*; D017951:Antigen Presentation / Q000235:genetics; D044466:Asian People / Q000235:genetics; D044383:Black People / Q000235:genetics; D015234:HLA-A Antigens / Q000235:genetics*; D006801:Humans; D017422:Sequence Analysis, DNA; D044465:White People / Q000235:genetics
D015234:HLA-A Antigens