title: HLA class I molecular variation and peptide-binding properties suggest a model of joint divergent asymmetric selection.
abstract: The main function of HLA class I molecules is to present pathogen-derived peptides to cytotoxic T lymphocytes. This function is assumed to drive the maintenance of an extraordinary amount of polymorphism at each HLA locus, providing an immune advantage to heterozygote individuals capable to present larger repertories of peptides than homozygotes. This seems contradictory, however, with a reduced diversity at individual HLA loci exhibited by some isolated populations. This study shows that the level of functional diversity predicted for the two HLA-A and HLA-B genes considered simultaneously is similar (almost invariant) between 46 human populations, even when a reduced diversity exists at each locus. We thus propose that HLA-A and HLA-B evolved through a model of joint divergent asymmetric selection conferring all populations an equivalent immune potential. The distinct pattern observed for HLA-C is explained by its functional evolution towards killer cell immunoglobulin-like receptor (KIR) activity regulation rather than peptide presentation.
authors.affiliation: Laboratory of Anthropology, Genetics and Peopling History, Department of Genetics and Evolution, Anthropology Unit, University of Geneva, Geneva, Switzerland. stephane.buhler@unige.ch.|Transplantation Immunology Unit & National Reference Laboratory for Histocompatibility, Department of Genetic and Laboratory Medicine, Geneva University Hospital, Geneva, Switzerland. stephane.buhler@unige.ch.
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), University of Geneva, Geneva, Switzerland.
authors.forename: José Manuel
authors.initials: JM
authors.lastname: Nunes
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), University of Geneva, Geneva, Switzerland.
authors.forename: Alicia
authors.initials: A
authors.lastname: Sanchez-Mazas
mesh_terms: D019143:Evolution, Molecular; D005805:Genes, MHC Class I / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D005828:Genetics, Population; D015236:HLA-C Antigens / Q000235:genetics* / Q000378:metabolism*; D006239:Haplotypes; D006801:Humans; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D040641:Quantitative Trait Loci; D054340:Receptors, KIR / Q000235:genetics / Q000378:metabolism*; D012641:Selection, Genetic / Q000235:genetics*
chemical_list: D015236:HLA-C Antigens; D010446:Peptide Fragments; D054340:Receptors, KIR
keywords: Asymmetric balancing selection; Functional variation; HLA class I polymorphism; Heterozygous advantage; Immune protection; Peptide-binding properties