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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...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5507469/ https://www.ncbi.nlm.nih.gov/pubmed/28650991 http://dx.doi.org/10.1371/journal.pgen.1006862 |
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author | Robinson, James Guethlein, Lisbeth A. Cereb, Nezih Yang, Soo Young Norman, Paul J. Marsh, Steven G. E. Parham, Peter |
author_facet | Robinson, James Guethlein, Lisbeth A. Cereb, Nezih Yang, Soo Young Norman, Paul J. Marsh, Steven G. E. Parham, Peter |
author_sort | Robinson, James |
collection | PubMed |
description | 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 α(1) and α(2) 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. |
format | Online Article Text |
id | pubmed-5507469 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-55074692017-07-25 Distinguishing functional polymorphism from random variation in the sequences of >10,000 HLA-A, -B and -C alleles Robinson, James Guethlein, Lisbeth A. Cereb, Nezih Yang, Soo Young Norman, Paul J. Marsh, Steven G. E. Parham, Peter PLoS Genet Research Article 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 α(1) and α(2) 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. Public Library of Science 2017-06-26 /pmc/articles/PMC5507469/ /pubmed/28650991 http://dx.doi.org/10.1371/journal.pgen.1006862 Text en © 2017 Robinson et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Robinson, James Guethlein, Lisbeth A. Cereb, Nezih Yang, Soo Young Norman, Paul J. Marsh, Steven G. E. Parham, Peter Distinguishing functional polymorphism from random variation in the sequences of >10,000 HLA-A, -B and -C alleles |
title | Distinguishing functional polymorphism from random variation in the sequences of >10,000 HLA-A, -B and -C alleles |
title_full | Distinguishing functional polymorphism from random variation in the sequences of >10,000 HLA-A, -B and -C alleles |
title_fullStr | Distinguishing functional polymorphism from random variation in the sequences of >10,000 HLA-A, -B and -C alleles |
title_full_unstemmed | Distinguishing functional polymorphism from random variation in the sequences of >10,000 HLA-A, -B and -C alleles |
title_short | Distinguishing functional polymorphism from random variation in the sequences of >10,000 HLA-A, -B and -C alleles |
title_sort | distinguishing functional polymorphism from random variation in the sequences of >10,000 hla-a, -b and -c alleles |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5507469/ https://www.ncbi.nlm.nih.gov/pubmed/28650991 http://dx.doi.org/10.1371/journal.pgen.1006862 |
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