title: Next-Generation Sequencing of the HLA locus: Methods and impacts on HLA typing, population genetics and disease association studies.
abstract: The human Major Histocompatibility Complex, known as the "Human Leukocyte Antigen (HLA)", could be defined as a "super locus" (historically called "supergene") governing the adaptive immune system in vertebrates. It also harbors genes involved in innate immunity. HLA is the most gene-dense, polymorphic and disease-associated region of the human genome. It is of critical medical relevance given its involvement in the fate of the transplanted organs/tissues and its association with more than 100 diseases. However, despite these important roles, comprehensive sequence analysis of the 4 megabase HLA locus has been limited due to technological challenges. Thanks to recent improvements in Next-Generation Sequencing (NGS) technologies however, one is now able to handle the peculiarities of the MHC notably the tight linkage disequilibrium between genes as well as their high degree of polymorphism (and hence heterozygosity). Increased read lengths, throughput, accuracy, as well as development of new bioinformatics tools now enable to efficiently generate complete and accurate full-length HLA haplotypes without phase ambiguities. The present report reviews current NGS approaches to capture, sequence and analyze HLA genes and loci. The impact of these new methodologies on various applications including HLA typing, population genetics and disease association studies are discussed.
authors.affiliation: Plateforme GENOMAX, Laboratoire d'ImmunoRhumatologie Moléculaire, INSERM UMR_S1109, LabEx Transplantex, Centre de Recherche d'Immunologie et d'Hématologie, Faculté de Médecine, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France; INSERM Franco-Japanese Nextgen HLA Laboratory (FJ-HLA), Laboratoire International Associé (LIA), Strasbourg, France; Fédération Hospitalo-Universitaire, OMICARE, Centre de Recherche d'Immunologie et d'Hématologie, 67085 Strasbourg Cedex, France; Laboratoire d'Immunologie, Plateau Technique de Biologie, Pôle de Biologie, Nouvel Hôpital Civil, 67091 Strasbourg Cedex, France. Electronic address: carapito@unistra.fr.
authors.forename: Raphael
authors.initials: R
authors.lastname: Carapito
authors.affiliation: Plateforme GENOMAX, Laboratoire d'ImmunoRhumatologie Moléculaire, INSERM UMR_S1109, LabEx Transplantex, Centre de Recherche d'Immunologie et d'Hématologie, Faculté de Médecine, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France; INSERM Franco-Japanese Nextgen HLA Laboratory (FJ-HLA), Laboratoire International Associé (LIA), Strasbourg, France; Fédération Hospitalo-Universitaire, OMICARE, Centre de Recherche d'Immunologie et d'Hématologie, 67085 Strasbourg Cedex, France; Laboratoire d'Immunologie, Plateau Technique de Biologie, Pôle de Biologie, Nouvel Hôpital Civil, 67091 Strasbourg Cedex, France.
authors.forename: Mirjana
authors.initials: M
authors.lastname: Radosavljevic
authors.affiliation: Plateforme GENOMAX, Laboratoire d'ImmunoRhumatologie Moléculaire, INSERM UMR_S1109, LabEx Transplantex, Centre de Recherche d'Immunologie et d'Hématologie, Faculté de Médecine, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France; INSERM Franco-Japanese Nextgen HLA Laboratory (FJ-HLA), Laboratoire International Associé (LIA), Strasbourg, France; Fédération Hospitalo-Universitaire, OMICARE, Centre de Recherche d'Immunologie et d'Hématologie, 67085 Strasbourg Cedex, France; Laboratoire d'Immunologie, Plateau Technique de Biologie, Pôle de Biologie, Nouvel Hôpital Civil, 67091 Strasbourg Cedex, France. Electronic address: siamak@unistra.fr.
authors.forename: Seiamak
authors.initials: S
authors.lastname: Bahram
mesh_terms: D056426:Genetic Loci / Q000235:genetics*; D005828:Genetics, Population; D055106:Genome-Wide Association Study; D005838:Genotype; D006680:HLA Antigens / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006650:Histocompatibility Testing; D006801:Humans; D015810:Linkage Disequilibrium; D011110:Polymorphism, Genetic
chemical_list: D006680:HLA Antigens
keywords: HLA; HLA typing; HLA-disease association; NGS; Population genetics