Distinguishing functional polymorphism from random variation in the sequences of >10,000 HLA-A, -B and -C alleles

HLA class I glycoproteins contain the functional sites that bind peptide antigens and engage lymphocyte receptors. Recently, clinical application of sequence-based HLA typing has uncovered an unprecedented number of novel HLA class I alleles. Here we define the nature and extent of the variation in...

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Bibliographic Details
Published in:PLoS genetics 2017-06, Vol.13 (6), p.e1006862-e1006862
Main Authors: Robinson, James, Guethlein, Lisbeth A, Cereb, Nezih, Yang, Soo Young, Norman, Paul J, Marsh, Steven G E, Parham, Peter
Format: Article
Language:English
Subjects:
Alleles
Amino acids
Antigens
Binding sites
Bioinformatics
Biology
Biology and Life Sciences
Clonal selection
Deoxyribonucleic acid
DNA
DNA Mutational Analysis
Fourier transforms
Funding
Genes
Genetic aspects
Genetic polymorphisms
Genetic variation
Genetics
Genetics, Population
Germ-Line Mutation - genetics
Glycoproteins
Histocompatibility antigen HLA
Histocompatibility Testing
HLA antigens
HLA-A Antigens - genetics
HLA-B Antigens - genetics
HLA-C Antigens - genetics
Homology
Humans
Immune system
Immunology
Incidence
Multilocus sequence typing
Mutation
Observations
Phylogenetics
Phylogeny
Physiological aspects
Point Mutation
Polymorphism
Polymorphism, Single Nucleotide
Population genetics
Positive selection
Recombinants
Research and Analysis Methods
Sequence Alignment
Single-nucleotide polymorphism
Software
Tissue typing
Typing
University colleges
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Summary:HLA class I glycoproteins contain the functional sites that bind peptide antigens and engage lymphocyte receptors. Recently, clinical application of sequence-based HLA typing has uncovered an unprecedented number of novel HLA class I alleles. Here we define the nature and extent of the variation in 3,489 HLA-A, 4,356 HLA-B and 3,111 HLA-C alleles. This analysis required development of suites of methods, having general applicability, for comparing and analyzing large numbers of homologous sequences. At least three amino-acid substitutions are present at every position in the polymorphic α1 and α2 domains of HLA-A, -B and -C. A minority of positions have an incidence >1% for the 'second' most frequent nucleotide, comprising 70 positions in HLA-A, 85 in HLA-B and 54 in HLA-C. The majority of these positions have three or four alternative nucleotides. These positions were subject to positive selection and correspond to binding sites for peptides and receptors. Most alleles of HLA class I (>80%) are very rare, often identified in one person or family, and they differ by point mutation from older, more common alleles. These alleles with single nucleotide polymorphisms reflect the germ-line mutation rate. Their frequency predicts the human population harbors 8-9 million HLA class I variants. The common alleles of human populations comprise 42 core alleles, which represent all selected polymorphism, and recombinants that have assorted this polymorphism.
ISSN:1553-7404
1553-7390
1553-7404
DOI:10.1371/journal.pgen.1006862