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About the Authors:
James Robinson
Roles Conceptualization, Data curation, Formal analysis, Software, Visualization, Writing - original draft, Writing - review & editing
Affiliations Anthony Nolan Research Institute, London, United Kingdom, UCL Cancer Institute, University College London, London, United Kingdom
ORCID http://orcid.org/0000-0002-2187-5944
Lisbeth A. Guethlein
Roles Conceptualization, Formal analysis, Visualization, Writing - original draft, Writing - review & editing
* E-mail: [email protected]
Affiliation: Dept. of Structural Biology & Dept. of Microbiology & Immunology, School of Medicine, Stanford University, Stanford, California, United States of America
ORCID http://orcid.org/0000-0002-1301-8301
Nezih Cereb
Roles Conceptualization, Resources, Writing - review & editing
Affiliation: Histogenetics, Ossining, New York, United States of America
Soo Young Yang
Roles Resources, Writing - review & editing
Affiliation: Histogenetics, Ossining, New York, United States of America
Paul J. Norman
Roles Formal analysis, Writing - original draft, Writing - review & editing
Affiliation: Dept. of Structural Biology & Dept. of Microbiology & Immunology, School of Medicine, Stanford University, Stanford, California, United States of America
ORCID http://orcid.org/0000-0001-8370-7703
Steven G. E. Marsh
Roles Conceptualization, Funding acquisition, Supervision, Writing - original draft, Writing - review & editing
Affiliations Anthony Nolan Research Institute, London, United Kingdom, UCL Cancer Institute, University College London, London, United Kingdom
Peter Parham
Roles Conceptualization, Funding acquisition, Supervision, Writing - original draft, Writing - review & editing
Affiliation: Dept. of Structural Biology & Dept. of Microbiology & Immunology, School of Medicine, Stanford University, Stanford, California, United States of AmericaAbstract
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 [alpha] 1 and [alpha] 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...