title: An evolutionary analysis of antigen processing and presentation across different timescales reveals pervasive selection.
abstract: The antigenic repertoire presented by MHC molecules is generated by the antigen processing and presentation (APP) pathway. We analyzed the evolutionary history of 45 genes involved in APP at the inter- and intra-species level. Results showed that 11 genes evolved adaptively in mammals. Several positively selected sites involve positions of fundamental importance to the protein function (e.g. the TAP1 peptide-binding domains, the sugar binding interface of langerin, and the CD1D trafficking signal region). In CYBB, all selected sites cluster in two loops protruding into the endosomal lumen; analysis of missense mutations responsible for chronic granulomatous disease (CGD) showed the action of different selective forces on the very same gene region, as most CGD substitutions involve aminoacid positions that are conserved in all mammals. As for ERAP2, different computational methods indicated that positive selection has driven the recurrent appearance of protein-destabilizing variants during mammalian evolution. Application of a population-genetics phylogenetics approach showed that purifying selection represented a major force acting on some APP components (e.g. immunoproteasome subunits and chaperones) and allowed identification of positive selection events in the human lineage. We also investigated the evolutionary history of APP genes in human populations by developing a new approach that uses several different tests to identify the selection target, and that integrates low-coverage whole-genome sequencing data with Sanger sequencing. This analysis revealed that 9 APP genes underwent local adaptation in human populations. Most positive selection targets are located within noncoding regions with regulatory function in myeloid cells or act as expression quantitative trait loci. Conversely, balancing selection targeted nonsynonymous variants in TAP1 and CD207 (langerin). Finally, we suggest that selected variants in PSMB10 and CD207 contribute to human phenotypes. Thus, we used evolutionary information to generate experimentally-testable hypotheses and to provide a list of sites to prioritize in follow-up analyses.
authors.affiliation: Scientific Institute IRCCS E. MEDEA, Bioinformatics, Bosisio Parini, Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: Forni
authors.affiliation: Scientific Institute IRCCS E. MEDEA, Bioinformatics, Bosisio Parini, Italy.
authors.forename: Rachele
authors.initials: R
authors.lastname: Cagliani
authors.affiliation: Scientific Institute IRCCS E. MEDEA, Bioinformatics, Bosisio Parini, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Tresoldi
authors.affiliation: Scientific Institute IRCCS E. MEDEA, Bioinformatics, Bosisio Parini, Italy.
authors.forename: Uberto
authors.initials: U
authors.lastname: Pozzoli
authors.affiliation: Department of Biotechnology and Biosciences, University of Milan-Bicocca, Milan, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: De Gioia
authors.affiliation: Department of Biotechnology and Biosciences, University of Milan-Bicocca, Milan, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Filippi
authors.affiliation: Scientific Institute IRCCS E. MEDEA, Bioinformatics, Bosisio Parini, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Riva
authors.affiliation: Scientific Institute IRCCS E. MEDEA, Bioinformatics, Bosisio Parini, Italy.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Menozzi
authors.affiliation: Scientific Institute IRCCS E. MEDEA, Bioinformatics, Bosisio Parini, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Colleoni
authors.affiliation: Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy.
authors.forename: Mara
authors.initials: M
authors.lastname: Biasin
authors.affiliation: Infectious Disease Unit, S. Maria Annunziata Hospital, Florence, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Lo Caputo
authors.affiliation: Infectious Disease Unit, S. Maria Annunziata Hospital, Florence, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Mazzotta
authors.affiliation: Dino Ferrari Centre, Department of Physiopathology and Transplantation, University of Milan, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Giacomo P
authors.initials: GP
authors.lastname: Comi
authors.affiliation: Scientific Institute IRCCS E. MEDEA, Bioinformatics, Bosisio Parini, Italy; Dino Ferrari Centre, Department of Physiopathology and Transplantation, University of Milan, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Nereo
authors.initials: N
authors.lastname: Bresolin
authors.affiliation: Chair of Immunology, Department of Physiopathology and Transplantation, University of Milan, Milan, Italy; Don C. Gnocchi Foundation ONLUS, IRCCS, Milan, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Clerici
authors.affiliation: Scientific Institute IRCCS E. MEDEA, Bioinformatics, Bosisio Parini, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Sironi
mesh_terms: D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000276:immunology; D000483:Alleles; D000818:Animals; D017951:Antigen Presentation / Q000235:genetics* / Q000276:immunology; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology; D019143:Evolution, Molecular; D005828:Genetics, Population; D006801:Humans; D037181:Lectins, C-Type / Q000235:genetics / Q000276:immunology; D008322:Mammals; D037241:Mannose-Binding Lectins / Q000235:genetics / Q000276:immunology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics / Q000276:immunology; D010802:Phylogeny; D012641:Selection, Genetic
chemical_list: D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters; D015703:Antigens, CD; C121916:CD207 protein, human; D037181:Lectins, C-Type; D037241:Mannose-Binding Lectins; D008562:Membrane Glycoproteins; C073119:TAP1 protein, human; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases