title: HLA supertype variation across populations: new insights into the role of natural selection in the evolution of HLA-A and HLA-B polymorphisms.
abstract: Supertypes are groups of human leukocyte antigen (HLA) alleles which bind overlapping sets of peptides due to sharing specific residues at the anchor positions-the B and F pockets-of the peptide-binding region (PBR). HLA alleles within the same supertype are expected to be functionally similar, while those from different supertypes are expected to be functionally distinct, presenting different sets of peptides. In this study, we applied the supertype classification to the HLA-A and HLA-B data of 55 worldwide populations in order to investigate the effect of natural selection on supertype rather than allelic variation at these loci. We compared the nucleotide diversity of the B and F pockets with that of the other PBR regions through a resampling procedure and compared the patterns of within-population heterozygosity (He) and between-population differentiation (G ST) observed when using the supertype definition to those estimated when using randomized groups of alleles. At HLA-A, low levels of variation are observed at B and F pockets and randomized He and G ST do not differ from the observed data. By contrast, HLA-B concentrates most of the differences between supertypes, the B pocket showing a particularly high level of variation. Moreover, at HLA-B, the reassignment of alleles into random groups does not reproduce the patterns of population differentiation observed with supertypes. We thus conclude that differently from HLA-A, for which supertype and allelic variation show similar patterns of nucleotide diversity within and between populations, HLA-B has likely evolved through specific adaptations of its B pocket to local pathogens.
authors.affiliation: Department of Genetics and Evolutionary Biology, University of São Paulo, São Paulo, Brazil. biorodrigo2001@yahoo.com.br.|Laboratory of Anthropology, Genetics and Peopling History, Department of Genetics and Evolution-Anthropology Unit, University of Geneva, Geneva, Switzerland. biorodrigo2001@yahoo.com.br.|Hospital Israelita Albert Einstein, São Paulo, Brazil. biorodrigo2001@yahoo.com.br.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Dos Santos Francisco
authors.affiliation: Laboratory of Anthropology, Genetics and Peopling History, Department of Genetics and Evolution-Anthropology Unit, University of Geneva, Geneva, Switzerland.|Transplantation Immunology Unit and National Reference Laboratory for Histocompatibility, Department of Genetic and Laboratory Medicine, Geneva University Hospital, Geneva, Switzerland.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Buhler
authors.affiliation: Laboratory of Anthropology, Genetics and Peopling History, Department of Genetics and Evolution-Anthropology Unit, University of Geneva, Geneva, Switzerland.|Institute of Genetics and Genomics in Geneva (IGE3), Geneva, Switzerland.
authors.forename: José Manuel
authors.initials: JM
authors.lastname: Nunes
authors.affiliation: Department of Genetics and Evolutionary Biology, University of São Paulo, São Paulo, Brazil.
authors.forename: Bárbara Domingues
authors.initials: BD
authors.lastname: Bitarello
authors.affiliation: Department of Biochemistry, Chemistry Institute, University of São Paulo, São Paulo, Brazil.|Molecular Oncology Center, Sírio-Libanês Hospital, São Paulo, Brazil.
authors.forename: Gustavo Starvaggi
authors.initials: GS
authors.lastname: França
authors.affiliation: Department of Genetics and Evolutionary Biology, University of São Paulo, São Paulo, Brazil. diogo@ib.usp.br.
authors.forename: Diogo
authors.initials: D
authors.lastname: Meyer
authors.affiliation: Laboratory of Anthropology, Genetics and Peopling History, Department of Genetics and Evolution-Anthropology Unit, University of Geneva, Geneva, Switzerland. alicia.sanchez-mazas@unige.ch.|Institute of Genetics and Genomics in Geneva (IGE3), Geneva, Switzerland. alicia.sanchez-mazas@unige.ch.
authors.forename: Alicia
authors.initials: A
authors.lastname: Sanchez-Mazas
mesh_terms: D005075:Biological Evolution; D003198:Computer Simulation; D016208:Databases, Factual; D005828:Genetics, Population; D015234:HLA-A Antigens / Q000145:classification / Q000235:genetics* / Q000276:immunology; D015235:HLA-B Antigens / Q000145:classification / Q000235:genetics* / Q000276:immunology; D006650:Histocompatibility Testing; D006801:Humans; D016056:Immunodominant Epitopes; D007390:International Agencies; D011110:Polymorphism, Genetic / Q000235:genetics*; D012641:Selection, Genetic / Q000235:genetics*
chemical_list: D015234:HLA-A Antigens; D015235:HLA-B Antigens; D016056:Immunodominant Epitopes
keywords: Adaptation; HLA; Human populations; Natural selection; Pathogens; Supertypes