title: Insights into HLA-G Genetics Provided by Worldwide Haplotype Diversity.
abstract: Human leukocyte antigen G (HLA-G) belongs to the family of non-classical HLA class I genes, located within the major histocompatibility complex (MHC). HLA-G has been the target of most recent research regarding the function of class I non-classical genes. The main features that distinguish HLA-G from classical class I genes are (a) limited protein variability, (b) alternative splicing generating several membrane bound and soluble isoforms, (c) short cytoplasmic tail, (d) modulation of immune response (immune tolerance), and (e) restricted expression to certain tissues. In the present work, we describe the HLA-G gene structure and address the HLA-G variability and haplotype diversity among several populations around the world, considering each of its major segments [promoter, coding, and 3' untranslated region (UTR)]. For this purpose, we developed a pipeline to reevaluate the 1000Genomes data and recover miscalled or missing genotypes and haplotypes. It became clear that the overall structure of the HLA-G molecule has been maintained during the evolutionary process and that most of the variation sites found in the HLA-G coding region are either coding synonymous or intronic mutations. In addition, only a few frequent and divergent extended haplotypes are found when the promoter, coding, and 3'UTRs are evaluated together. The divergence is particularly evident for the regulatory regions. The population comparisons confirmed that most of the HLA-G variability has originated before human dispersion from Africa and that the allele and haplotype frequencies have probably been shaped by strong selective pressures.
authors.affiliation: Department of Pathology, School of Medicine of Botucatu, Universidade Estadual Paulista , Botucatu , Brazil.
authors.forename: Erick C
authors.initials: EC
authors.lastname: Castelli
authors.affiliation: Department of Pathology, School of Medicine of Botucatu, Universidade Estadual Paulista , Botucatu , Brazil.
authors.forename: Jaqueline
authors.initials: J
authors.lastname: Ramalho
authors.affiliation: Department of Pathology, School of Medicine of Botucatu, Universidade Estadual Paulista , Botucatu , Brazil.
authors.forename: Iane O P
authors.initials: IO
authors.lastname: Porto
authors.affiliation: Department of Pathology, School of Medicine of Botucatu, Universidade Estadual Paulista , Botucatu , Brazil.
authors.forename: Thálitta H A
authors.initials: TH
authors.lastname: Lima
authors.affiliation: Biological Sciences Institute, Federal University of Goias , Goiânia , Brazil.
authors.forename: Leandro P
authors.initials: LP
authors.lastname: Felício
authors.affiliation: UMR 216, Institut de Recherche pour le Développement, MERIT , Paris , France ; Faculté de Pharmacie, Université Paris Descartes, Sorbonne Paris Cité , Paris , France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Sabbagh
authors.affiliation: Division of Clinical Immunology, Department of Medicine, School of Medicine of Ribeirão Preto, University of São Paulo , Ribeirão Preto , Brazil.
authors.forename: Eduardo A
authors.initials: EA
authors.lastname: Donadi
authors.affiliation: Departamento de Química, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, University of São Paulo , Ribeirão Preto , Brazil.
authors.forename: Celso T
authors.initials: CT
authors.lastname: Mendes-Junior
keywords: 1000Genomes Project; HLA-G; gene structure and diversity; haplotypes; non-classical HLA; polymorphisms; selective pressure; variability